Substituted morpholine derivatives and pharmaceutical compositions

ABSTRACT

Substituted morpholine derivatives, such as, for instance the compound 2-[α-(3,4-methylendioxy-phenoxy)-benzyl]-morpholine are disclosed. 
     The claimed compounds are active on the central nervous system, and may be used as antidepressant agents.

This is a divisional application of Ser. No. 1,604, filed Jan. 8, 1979now U.S. Pat. No. 4,229,449.

The present invention relates to substituted propanolamine andmorpholine derivatives, to a process for their preparation and topharmaceutical compositions containing them.

The compounds covered by this invention have the general formula (I)##STR1## wherein n and n₁ are, independently, 1, 2 or 3;

each or the groups R and R₁, which may be the same or different, ishydrogen; halogen; halo-C₁ -C₆ alkyl; hydroxy; C₁ -C₆ alkoxy; C₁ -C₆alkyl optionally substituted; aryl-C₁ -C₆ alkyl optionally substituted;aryl-C₁ -C₆ alkoxy optionally substituted; --NO₂ ; ##STR2## wherein R₅and R₆ are, independently, hydrogen or C₁ -C₆ alkyl, or two adjacent Rgroups or two adjacent R₁ groups, taken together, form the --O--CH₂--O-- radical;

R₂ is hydrogen; C₁ -C₁₂ alkyl optionally substituted, or aryl-C₁ -C₆alkyl;

each of the groups R₃ and R₄, which may be identical or different, ishydrogen, C₁ -C₆ alkyl optionally substituted, C₂ -C₄ alkenyl, C₂ -C₄alkynyl, aryl-C₁ -C₄ alkyl optionally substituted, C₃ -C₇ cycloalkyloptionally substituted, or R₃ and R₄ with the nitrogen atom to whichthey are bounded form a pentatomic or hexatomic saturated orunsaturated, optionally substituted, heteromonocyclic radical optionallycontaining other heteroatoms belonging to the class of O, S and N;

or R₂ and R₄, taken together, form the --CH₂ --CH₂ -- radical.

This invention also includes the pharmaceutically acceptable salts ofcompounds with formula (I) as well as all the possible isomers and theirmixtures, the metabolites provided with pharmacological, e.g.antidepressant, activity and the metabolic precursors of the compoundswith formula (I).

The alkyl, alkenyl, alkynyl and alkoxy groups may be straight orbranched chains.

When one or more of the groups R and R₁ is a substituted C₁ -C₆ alkylgroup, it is preferably C₁ -C₆ alkyl substituted by one or moresubstituents chosen from hydroxy, C₁ -C₆ alkoxy, ##STR3## group, inwhich R₅ and R₆ are as defined above.

An aryl group is preferably phenyl.

When one or more of the groups R₃ and R₄ is a substituted C₁ -C₆ alkylgroup it is preferably C₁ -C₆ alkyl substituted by one or moresubstituents chosen from halogen, hydroxy, C₁ -C₆ alkoxy, ##STR4## withR₅ and R₆ as defined above. The same substituents may be present on asubstituted C₁ -C₁₂ alkyl group.

Substituted aryl-C₁ -C₆ alkyl, aryl-C₁ -C₄ alkyl and aryl-C₁ -C₆ alkoxygroups are preferably aryl-C₁ -C₆ alkyl, aryl-C₁ -C₄ alkyl and aryl-C₁-C₆ alkoxy groups in which the aryl group is substituted by one or moreC₁ -C₆ alkyl, halogen, halo-C₁ -C₆ alkyl, hydroxy, C₁ -C₆ alkoxy and##STR5## with R₅ and R₆ as defined above.

A substituted C₃ -C₇ cycloalkyl group is a C₃ -C₇ cycloalkyl substitutedby one or more substituents preferably chosen from C₁ -C₆ alkyl,halogen, halo-C₁ -C₆ -alkyl, hydroxy, C₁ -C₆ alkoxy and ##STR6## inwhich R₅ and R₆ are as defined above.

A C₁ -C₆ alkyl group is preferably methyl, ethyl or isopropyl.

A C₁ -C₁₂ alkyl group is preferably methyl, ethyl, isopropyl or octyl.

A C₂ -C₄ alkenyl group is preferably vinyl or allyl.

A C₂ -C₄ alkynyl group is preferably propargyl.

A halo-C₁ -C₆ alkyl group is preferably trihalo-C₁ -C₆ alkyl, inparticular trifluoromethyl.

A C₁ -C₆ alkoxy group is preferably methoxy or ethoxy.

An aryl-C₁ -C₆ alkyl or aryl-C₁ -C₄ alkyl group is preferably benzyl orphenethyl.

An aryl-C₁ -C₆ alkoxy group is preferably benzyloxy.

In a ##STR7## group, R₅ and R₆ preferably are, independently, hydrogenor C₁ -C₃ alkyl, in particular methyl, ethyl or isopropyl.

A C₃ -C₇ cycloalkyl group is preferably cyclopropyl, cyclopentyl orcyclohexyl. When R₃ and R₄, with the nitrogen atom to which they arelinked, form a substituted heteromonocyclic radical, the substituentsare preferably C₁ -C₆ alkyl or aryl, in particular methyl or phenyl;preferred heteromonocyclic radicals are morpholino, piperidino,N-pyrrolidinyl, N-methyl-piperazinyl and N-phenyl-piperazinyl.

When two adjacent R groups or two adjacent R₁ groups form the --O--CH₂--O-- radical, this is preferably a 3,4-methylendioxy radical.

Owing to the presence of at least two asymmetric carbon atoms, for eachcompound of formula (I) at least two distinct diastereoisomers mayexist, from which at least four distinct enantiomers may be obtained:both the single diastereoisomers and their mixture as well as the singleenantiomers are included in the object of this invention.

Examples of pharmaceutically acceptable salts of compounds (I) are boththe salts with inorganic acids, for example hydrochloric acid,hydrobromic acid, sulphuric acid, and the salts with organic acids, forexample, citric acid, tartaric acid, methansulphonic acid, fumaric acid,malic acid, maleic acid and mandelic acid.

According to this invention preferred salts of compounds (I) are thosein which the ##STR8## group is salified with one of the acids mentionedabove, preferably the hydrochloric acid.

Preferred compounds of the invention are the compounds with formula (I)wherein n and n₁ are independently 1 or 2; each of the groups R and R₁is, independently, hydrogen, methoxy, ethoxy, chlorine, trifluoromethylor two adjacent R groups form a --O--CH₂ --O-- radical; R₂ is hydrogenor methyl; one of the groups R₃ and R₄ is hydrogen and the other ismethyl as well as the pharmaceutically acceptable salts thereof.

Particularly preferred compounds of the invention are the compounds withformula (I) wherein n and n₁ are, independently 1 or 2; each of thegroups R and R₁ is, independently, hydrogen, methoxy, ethoxy, chlorine,trifluoromethyl or two adjacent R groups form the radical --O--CH₂--O--; R₂ and R₄, taken together, form the radical --CH₂ --CH₂ --, R₃ ishydrogen, methyl or isopropyl as well as the pharmaceutically acceptablesalts thereof.

Examples of compounds preferred under this invention are:

2-(α-phenoxy-benzyl)-morpholine;

2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine;

2-[α-(3-methoxy-phenoxy)-benzyl]-morpholine;

2-[α-(4-methoxy-phenoxy)-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-benzyl]-morpholine;

2-[α-(3,4-methylendioxy-phenoxy)-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-2-chloro-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-3-chloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(4-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

N-methyl-2-hydroxy-3-phenoxy-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(4-chloro-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(3,4-methylenedioxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(4-chloro-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine;N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine,as well as their pharmaceutically acceptable salts.

The compounds of the invention are prepared by a process comprising:

(a) reducing a compound of formula (II) ##STR9## wherein n, n₁, R, R₁and R₂ are as defined above, so obtaining compounds of formula (I)wherein R₃ and R₄ are both hydrogen and R, R₁, n, n₁ and R₂ are asdefined above; or

(b) reducing a compound of formula (III) ##STR10## wherein n, n₁, R, R₁,R₂, R₃ and R₄ have the meanings reported above; or

(c) reducing a compound of formula (IV) ##STR11## wherein n, n₁ and R₂are as defined above and R and R₁ have the meanings reported aboveexcept --NO₂, or a salt thereof, so obtaining compounds of formula (I)wherein n, n₁ and R₂ are as defined above, R and R₁ have the meaningsreported above except --NO₂, and R₃ and R₄ are both hydrogen; or

(d) reacting a compound of formula (V) ##STR12## wherein n, n₁, R and R₁are as defined above, with an amine of formula HNR₃ R₄ in which R₃ andR₄ are as defined above, so obtaining compounds with formula (I) whereinR₂ is hydrogen, n, n₁, R, R₁, R₃ and R₄ have the meanings reportedabove, except the meaning of R₄ as forming, together with R₂, theradical --CH₂ --CH₂ --; or

(e) reducing a compound of formula (VI) ##STR13## wherein n, n₁, R, R₁and R₃ are as defined above, and Z is >CH₂ or >C═O, so obtainingcompounds of formula (I) wherein R₂ and R₄, taken together, form theradical --CH₂ --CH₂ -- and n, n₁, R, R₁ and R₃ are as defined above; or

(f) reductively cyclizing a compound of formula (VII) ##STR14## whereinn, n₁, R and R₁ are as defined above, R_(a) is C₁ -C₆ -alkyl, one ofR_(b) and R_(c) is hydrogen and the other is --C.tbd.N or R_(b) andR_(c), taken together, form the radical ═CH--NO₂, so obtaining compoundsof formula (I) wherein n, n₁, R and R₁ are as defined above, R₂ and R₄,taken together, form the radical --CH₂ --CH₂ -- and R₃ is hydrogen; or

(g) cyclizing a compound of formula (VIII) ##STR15## wherein n, n₁, R,R₁ and R₃ are as defined above and X is hydroxy or halogen or theresidue of a reactive ester of an alcohol, so obtaining compounds offormula (I) wherein R₂ and R₄, taken together, form the radical --CH₂--CH₂ -- and n, n₁, R, R₁ and R₃ are as defined above; or

(h) reacting a compound of formula (IX) ##STR16## wherein n, n₁, R, R₁and R₃ are as defined above, with a compound of formula (X)

    Y--CH.sub.2 --CH.sub.2 --Y                                 (X)

wherein each of the groups Y, whether the same or different, is halogenor the residue of a reactive ester of an alcohol, so obtaining compoundsof formula (I) wherein R₂ and R₄, taken together, form the radical --CH₂--CH₂ -- and n, n₁, R, R₁ and R₃ are as defined above and, if desired,converting a compound with formula (I) into another compound withformula (I) and/or, if desired, salifying a compound with formula (I) orobtaining a free compound from a salt and/or, if desired, resolving amixture of isomers into the individual isomers.

The reduction of a compound of formula (II) as well as the reduction ofa compound of formula (III) may be, in general, effected by the methodsusually employed for the reduction of nitriles and amides, for exampleby treatment with LiAlH₄ or BH₃ in an inert anhydrous solvent,preferably an aliphatic ether, e.g. diethyl ether, or tetrahydrofuran,or a mixture of these solvents at temperatures varying from about 0° C.to solvent reflux temperature, or by treatment with an alkalineboronhydride, e.g. NaBH₄, in the presence of alkaline metals asdescribed, for example, in Tetr. Lett. 1969, page 4555. Alternativelythe reduction of a compound of formula (II) may be carried out bycatalytic hydrogenation using, e.g., Raney nickel or Pd/C as catalystand operating in the presence of liquid ammonia in a solvent which maybe, for example, a C₁ -C₆ -aliphatic alcohol, e.g. methanol or ethanol,or the water at atmospheric pressure and at temperatures ranging fromroom temperature to about 50° C.

A salt of a compound of formula (IV) is, for example, the salt of acompound of formula (IV) in which R₂ is hydrogen with an alkaline metal,e.g. sodium or potassium: this salt can be obtained directly in thecourse of the preparation of the compound (IV) described later.

The reduction of a compound of formula (IV) or a salt thereof may beperformed by conventional way, for example with LiAlH₄ as described,e.g., in J. Org. Chem. 39, page 2852 (1974) or with sodiumbis-(2-metoxyetoxy)aluminiumdihydride, i.e. NaAlH₂ (OC₂ H₄ OCH₃)₂, asreported, e.g., in Chem. Comm. 1974, page 307. The reaction of acompound of formula (V) with an amine of formula HNR₃ R₄ may be effectedby known methods, preferably without solvents but also in the presenceof a solvent such as, for example, an aqueous or aqueous-alcoholicsolvent or dimethylformamide, operating, if necessary, in a stoppedvessel, at temperatures ranging from room temperature to approximately150° C.

The reduction of a compound of formula (VI) may be performed by the samemethod reported above for the reduction of a compound of formula (III)using, for example, the procedure described in J. Med. Chem., vol 19,page 41 (1976), particularly when Z, in the compound (VI), represents agroup >C═O.

The reductive cyclization of a compound of formula (VII) may be carriedout by treatment with a suitable reducing agent by known procedures,preferably with BH₃ in an inert anhydrous solvent, e.g. an aliphaticether, for example diethylether, or tetrahydrofuran, at temperaturesvarying preferably between about 0° C. and about 40° C.

When in the compound of formula (VIII) X is halogen this is preferablychlorine or bromine, when X is the residue of a reactive ester of analcohol, it is preferably --O--mesyl or --O--tosyl.

The cyclization of a compound of formula (VIII) may be effected byconventional way, for example, when X is hydroxy, by boiling in asolvent able to form an azeotropic mixture with water, e.g. toluene, inthe presence of an acid catalyst, e.g. p-toluensulphonic acid or BF₃and/or in the presence of a dehydrating agent, e.g. anhydrous CuSO₄ ; or3 when X is halogen or the residue of a reactive ester of an alcohol, bytreatment with a base, for example with potassium tert. butylate intert. butyl alcohol or with sodium hydride in dimethylformamide,dimethylsulphoxyde or dimethylacetamide, or with butyl lithium orlithium diisopropylamine and simiilar in tetrahydrofuran or in analiphatic ether, e.g. diethylether, or with NaNH₂ or KNH₂ in ammoniausing the procedures known in the organic chemistry.

When in the compound of formula (VIII) one or more of the substituents Rand R₁ represents an hydroxy group, in order to avoid that this groupinterfere in the cyclization reaction, an amount of base sufficient tosalify all the hydroxy groups present is preferably employed: thereactivity of the alcoholic salified hydroxy group is higher than thatof the salified phenolic hydroxy group which therefore does notinterfere in the reaction.

In a compound of formula (X) preferably the groups Y are both halogen,and in this case preferably one of them is chlorine and the other isiodine, or they are both --O--tosyl, or, preferably, they are both--O--mesyl.

The reaction of a compound of formula (IX) with a compound of formula(X) wherein the groups Y are both halogen, in particular with1-chloro-2-iodo-ethane, may be performed, for example, usingequimolecular amounts of the reagents in presence of an amount at leastequimolecular of a strong base preferably chosen from the group of thealkaline hydrides, e.g. sodium hydride, or of a small excess of analkaline or alkaline-earth carbonate or bicarbonate, e.g. Na₂ CO₃, K₂CO₃ or NaHCO₃. The used solvent preferably is a polar solvent, forexample dimethylformamide, and the reaction temperature may vary fromroom temperature to solvent reflux temperature, preferably arounding 50°C.

The reaction of a compound of formula (IX) with a compound of formula(X) wherein both the groups Y represent the residue of a reactive esterof an alcohol, in particular --O--mesyl, may be carried out by treating,under cooling, the mixture containing equimolecular amounts of thereagents in an apolar solvent, e.g. benzene or an aliphatic ether, forexample diethylether, with at least two molar equivalents of a strongbase such as, for example, butyl lithium, lithium isopropylamide orsodium amide in ammonia.

The interference in the reaction between compounds (IX) and compounds(X) of the hydroxy groups in case represented by the substituents R andR₁ can be avoided using an excess of the base analogously to whatreported above in connection with the cyclization of a compound offormula (VIII).

When in the compounds having the formulae (II), (III), (IV), (VI) and(VII) reported above one or more of the substituents R, R₁, R₃ and R₄represent reducible groups and we wish to maintain these groupsunchanged in the final compounds (I), then the reductions reported aboveat the points (a), (b), (c), (e) and (f) are preferably performed usingselective conditions.

Thus, for example, the reduction of compounds with formula (II), (III),(VI) and (VII) containing groups halogen or nitro may be effectedselectively as to these groups operating, for example, with BH₃ intetrahydrofuran or an aliphatic ether, e.g. diethylether, under nitrogenatmosphere, for example according to the procedure described in J. Am.Chem. Soc. 86, 3566 (1964) or also with Zn in ethanol as described inExperientia 33 (I), 101-102 (1977). The reduction of a compound offormula (IV) wherein one or more of the groups R and R₁ is halogen maybe carried out selectively as to the halogen using, e.g., Red-Al, i.e.NaAlH₂ (OC₂ H₄ OCH₃)₂, as reducing agent. The reduction of compounds offormula (III) and (VI) wherein R₃ or R₄ is C₂ -C₄ alkenyl or C₂ -C₄alkynyl may be carried out selectively as to these groups using, e.g.,LiAlH₄ in the reaction conditions previously reported. However, in theseconditions NO₂ -groups and halogen atoms, in case present, are reducedtoo, therefore compounds (I) wherein one or more of the substituents Rand R₁ represents a nitro group or a halogen atom and R₃ represents, atthe same time, C₂ -C₄ -alkenyl or C₂ -C₄ -alkynyl cannot be prepared bythe reduction processes reported above. These compounds may be obtained,for example, by the processes indicated above at the points (d), (g) or(h) or by conversion of a compound of formula (I) into another compoundof formula (I).

The same considerations apply to the other reductive processes describedin the present application either whether they regard the preparation offinal compounds or whether they regard the preparation of intermediatecompounds. Both the optional conversion of a compound of formula (I)into another compound of formula (I) and the optional salification orthe preparation of a free compound of formula (I) from a salt thereof aswell as the optional resolution of a mixture of isomers can be effectedby conventional way.

For example, a compound of formula (I) wherein R₃ is hydrogen and R₄ hasthe meanings reported above or, together with R₂, form a group --CH₂--CH₂ -- may be converted into the corresponding compound of formula (I)wherein R₃ is C₁ -C₆ -alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, aryl-C₁ -C₄alkyl or C₃ -C₇ cycloalkyl by the usual methods of alkylation of theamines for example the reductive amination or the mere alkylation.

The reductive amination consists in reacting a compound of formula (I)wherein R₃ and/or R₄ is hydrogen with the suitable carbonyl compound,that is aldehyde or ketone, in the presence of a reducing agent whichmay be the hydrogen or, preferably, a mixed hydride, e.g. NaBH₃ CN orNaBH₄, or the formic acid according to the Leuckart-Wallach reaction.

When the reducing agent is the hydrogen the reductive amination ispreferably carried out in an alcoholic solvent, e.g. methanol orethanol, in the presence of a catalyst such as, e.g., Raney nickel orPd/C at atmospheric pressure and at temperature varying from roomtemperature to about 50° C. according to the procedure described, e.g.,in Org. Reactions, 4, 174 (1948). When the reducing agent is a mixedhydride, e.g. NaBH₃ CN or NaBH₄, the reductive amination may be effectedin the presence of an excess of the hydride operating preferably at roomtemperature according to the methods described in Tetr. Lett., 3, 261(1963), J. Org. Chem., 37, 1673 (1972), Synthesis, 3, 140 (1975). Whenthe reductive amination is carried out with the formic acid according tothe Leuckart-Wallach reaction, the formic acid may be present in excessand the reaction mixture may be preferably heated for a time varyingfrom two to twelve hours as described, e.g., in Org. Reactions, 5, 301(1949).

The alkylation reaction may be performed, for example, by treatment withthe appropriate alkyl or aralkyl halide or with a reactive ester, e.g.tosylate or mesylate, of the appropriate alcohol. The alkylation may becarried out either in the absence of solvents or in a solvent such as,e.g., water, an aliphatic alcohol, e.g. ethyl or methyl alcohol, aglycol, e.g. ethylenic or propylenic glycol, benzene ordimethylformamide or a mixture of these solvents in the presence of anacid acceptor such as, for example, triethylamine, an alkaline carbonateor bicarbonate or an excess of the amine, at temperatures ranging fromabout 60° C. to solvent reflux temperature according to the proceduresdescribed, e.g., in J. Org. Chem. 2, 139 (1938); Org. Synt. Coll., vol.II, 183 (1943); J. Amer. Chem. Soc., 54, 4457 (1932).

The monoalkylation may be effected, alternatively, by the methodsdescribed for example in J. Org. Chem. 40, 23, 3453 (1975); J. Chem.Soc. c 2223 (1969); J. Med. Chem. 17 (1), 654 (1974).

The conversion of a compound of formula (I) wherein one of R₃ and R₄ ishydrogen into the corresponding compound of formula (I) wherein one ofR₃ and R₄ is methyl may be carried out in particular, also be reactionwith ethyl chloroformiate in chloroform, in the presence of an excess ofKOH at a temperature ranging from about 0° C. to about 5° C. and byreduction of the obtained carbamic ester with an excess of LiAlH₄ or BH₃in anhydrous diethylether at the reflux temperature.

A compound of formula (I) wherein one of R₃ and R₄ is C₁ -C₆ alkyl andthe other is hydrogen may be obtained, alternatively: (a') reacting acompound of formula (I) wherein both R₃ and R₄ are hydrogen withbenzaldehyde in a solvent such as, e.g., benzene or toluene at thereflux temperature; (b') reducing the obtained Schiff base, for exampleby catalytic hydrogenation in an alcoholic solvent in the presence ofRaney nickel or Pd/C, or with mixed hydrides, e.g. LiAlH₄ or NaBH₄, asdescribed, for example, in Houben-Weyl, vol. XI, part 1, page 341(1957); (c') alkylating the obtained benzylamine with the appropriatealkyl halide by the alkylation procedure previously described andfinally (d') removing the benzyl group, for example by catalytichydrogenation, according to the procedure described in J. Amer. Chem.Soc. 63, 1964 (1941), or, preferably, by treatment with ethylchloroformiate at the reflux temperature according to the methoddescribed in J. Med. Chem. 18(6), 576 (1975 ). By proceding analogouslya compound of formula (I) where one of R₃ and R₄ is benzyl may beconverted into the corresponding compound of formula (I) wherein one ofR₃ and R₄ is hydrogen. A compound of formula (I) where R₃ and R₄ areboth hydrogen may be converted into the corresponding compound offormula (I) wherein one of R₃ and R₄ is hydrogen and the other is benzylby reaction with benzoyl chloride in the presence of aqueous sodiumhydroxyde in an organic solvent such as, e.g., dichloromethanepreferably at temperatures varying from 0° C. to room temperature andthen reducing the obtained benzoylamino derivative with a mixed hydride,e.g. LiAlH₄ or BH₃ in tetrahydrofuran or diethylether at the solventreflux temperature.

A compound of formula (I) wherein R₂ is hydrogen may be converted into acompound of formula (I) wherein R₂ is C₁ -C₁₂ alkyl or aryl-C₁ -C₆ alkylby the methods usually employed for the etherification of the alcohols,for example reacting an alkaline salt of the alcohol, e.g. the lithiumor the sodium salt, with the appropriate alkyl or aralkyl halide; thereaction may be carried out at a temperature varying from the room tothe reflux temperature in an organic solvent which may be, for example,the same solvent wherein the alkaline salt of the alcohol was prepared.

The lithium salt of the alcohol may be obtained by reaction with alithium alkyl, e.g., lithium butyl, in an inert anhydrous solvent suchas, e.g., tetrahydrofuran; the sodium salt may be obtained by reactionwith sodium metal or sodium hydride in an inert anhydrous solvent suchas, e.g., benzene, toluene or dimethylformamide. By analogous way acompound of formula (I) where one of the groups R and R₁ is hydroxy maybe converted into the corresponding compound of formula (I) where one ofthe groups R and R₁ is C₁ -C₆ alkoxy or aryl-C₁ -C₆ alkoxy.

A compound of formula (I) where R₂ is C₁ -C₆ alkoxy or aryl-C₁ -C₆alkoxy may be converted into the corresponding compound of formula (I)where R₂ is hydroxy by the usual methods of de-etherification; forexample a compound of formula (I) where R₂ is methoxy may bede-etherified by treatment with pyridine hydrochloride or with borontribromide or with C₂ H₅ SK in dimethylformamide at 100°-130° C. asdescribed, e.g., in J. Med. Chem. 20(1), 165 (1977). When thede-etherification is carried out with piridine hydrochloride it ispreferably performed under nitrogen atmosphere at temperatures arounding150° C. The de-etherification with boron tribromide is preferablycarried out by adding to a solution of the compound of formula (I),cooled at a temperature between -70° and -80° C., a solution of BBr₃ inchloroform operating under nitrogen atmosphere and terminating thereaction at 0° C. by addition of methyl alcohol.

A compound of formula (I) where R₃ and R₄ are both methyl may beconverted into the corresponding compound of formula (I) where one of R₃and R₄ is methyl and the other is hydrogen, for example, by treatmentwith ethyl chloroformiate in benzene or toluene at the solvent refluxtemperature and by subsequent treatment with alcoholic KOH at the refluxtemperature.

A compound of formula (I) where one of the substituents R and R₁ is agroup --NO₂ may be converted into the corresponding compound of formula(I) wherein one of the groups R and R₁ is --NH₂ by the methods usuallyemployed for the reduction of the aromatic nitro-derivatives, forexample by catalytic hydrogenation using, e.g., platinum, palladium orRaney nickel as catalyst according to the known procedures of theorganic chemistry.

A compound of formula (I) where one of the substituents R and R₁ isamino may be transformed into the corresponding compound of formula (I)where one of the groups R and R₁ is hydroxy, converting the amine intothe corresponding diazonium salt and then hydrolysing this for exampleaccording to the procedure described in Org. Synth. 23, 11 (1943), or asdescribed in J. Org. Chem. 42, 2053 (1977).

A compound of formula (I) where one of the groups R and R₁ is amino maybe converted into the corresponding compound of formula (I) wherein oneof the groups R and R₁ is mono- or di-C₁ -C₆ alkylamino by reductiveamination or by alkylation as previously reported. As stated above alsothe salification of a compound of formula (I) as well as the preparationof a free compound from its salt and the separation of the isomers froma mixture may be effected in a conventional manner.

Thus, for example, the salt of a compound of formula (I) withhydrochloric acid may be obtained by treatment with anhydrous gaseoushydrochloric acid or an anhydrous alcoholic solution of hydrochloricacid in an anhydrous solvent such as, e.g., diethylether, benzene, ethylalcohol and isolating the hydrochloride by filtration or evaporation ofthe solvent.

The separation of the isomers, e.g. diastereoisomers, from their mixturemay be performed by fractionate cristallization from a suitable solventor by chromatography.

The chromatographic separation may be carried out both by thin layerpreparative chromatography and by column chromatography using silica gelor magnesium silicate as support and, e.g., benzene, ethyl acetate,cyclohexane, chloroform, methylene chloride, ethyl ether or theirmixtures as elution solvents, or by HPLC.

The optional conversions reported above for the compounds of formula (I)as well as the separation of the isomers, e.g. diastereoisomers, from amixture may also be effected, if desired, on the starting materials oron the intermediate compounds.

The compounds of formula (II) where R₂ is hydrogen may be prepared fromthe aldehydes of formula (XI) ##STR17## where R, R₁, n and n₁ are asdefined above, by the methods usually employed for converting thealdehydes into cyanohydrins, for example by treatment with ametabisulfite, preferably an alkaline, e.g. sodium, metabisulfite in thepresence of a cyanide preferably an alkaline, e.g. sodium or potassium,cyanide, operating in a suitable solvent such as, e.g., diethylenglycoldimethylether, water, an aliphatic alcohol, e.g. ethyl alcohol, or amixture of these solvents, at temperatures ranging from room temperatureto about 100° C., preferably from 50° C. to about 90° C.

The compounds of formula (II) where R₂ is C₁ -C₁₂ alkyl optionallysubstituted or aryl-C₁ -C₆ alkyl may be obtained by etherification ofthe compounds of formula (II) where R₂ is hydrogen according to theconventional procedures, e.g. by treating the alkaline salt of thealcohol with the appropriate alkyl or aralkyl halide as previouslyreported for the analogous conversions on compounds of formula (I). Thecompounds of formula (III) wherein R₂, R₃ and R₄ have the meaningsreported above except the meaning of R₂ and R₄ as forming, takentogether, --CH₂ --CH₂ --, may be prepared by the usual methods ofpreparation of the amides, for example by reacting an amine of formulaHNR₃ R₄ where R₃ and R₄ are as defined above, with a compound of formula(XII) ##STR18## where R, R₁, n, n₁ and R₂ are as defined above, or,preferably, with a reactive derivative thereof, for example an acidhalide or a C₁ -C₆ -alkyl-, preferably ethyl-, ester. The reaction maybe carried out either in the absence of solvent or in the presence of asuitable solvent such as, e.g., a C₁ -C₆ aliphatic alcohol, for exampleethyl alcohol, in the presence, if necessary, of a condensing agent,e.g. dicyclohexyl carbodiimide, or of an acid acceptor, for example analkaline carbonate or bicarbonate or a tertiary amine, e.g.triethylamine, or an excess of the amine of formula HNR₃ R₄.

The compounds of formula (III) wherein R₂ and R₄, taken together, formthe radical --CH₂ --CH₂ -- may be prepared, for example, by cyclizing acompound of formula (XIII) ##STR19## where R, R₁, n, n₁ and R₃ have themeanings reported above and X is hydroxy or halogen or, preferably, theresidue of a reactive ester of an alcohol, e.g. a tosylate or amesylate, operating for example, in the reaction conditions reportedabove for the cyclization of a compound of formula (VIII), preferably,when X is halogen or the residue of a reactive ester of an alcohol, inthe presence of an amount at least equimolecular of a base preferablychosen from the group of the alkaline carbonates and bicarbonates, e.g.K₂ CO₃, in a suitable solvent, e.g. dimethylformamide,dimethylsulphoxyde and similar.

Compounds of formula (III) wherein R₂ and R₄, taken together, form theradical --CH₂ --CH₂ -- may be also obtained, alternatively, from acompound of formula (XIV) ##STR20## where R, R₁, n, n₁ and R₃ are asdefined above, by heating at temperatures ranging from about 120° toabout 180° C. in an appropriate solvent such as, e.g.,hexamethylenphosphortriamide, as described, for example in Can. J. Chem.49, 914 (1971).

The compounds of formula (IV) may be prepared by treating, for example,a reactive derivative of the compound of formula (XII), which may be,for instance, one of the reactive derivatives indicated above or,preferably, the amide obtained by reacting the acid of formula (XII)with carbonyldiimidazole, with nitromethane in the presence of a basesuch as, e.g. an alkaline hydride, for example sodium hydride, in anappropriate anhydrous solvent, e.g. tetrahydrofuran. In this waycompounds of formula (IV) in which R₂ is the cation of the used base areobtained, which, if desired, may be etherified by conventional methods,for example as reported above, to give compounds of formula (IV) whereR₂ is C₁ -C₁₂ alkyl optionally substituted or aryl-C₁ -C₆ alkyl, oracidified to give the ketonic form of the compounds of formula (IV)where R₂ is hydrogen.

The compounds of formula (V) may be prepared by known methods, forexample oxidizing a compound of formula (XV) ##STR21## where R, R₁, nand n₁ are as defined above, for example with a peroxy acid, preferablym-chloro-perbenzoic acid, in an organic solvent, e.g. dichloromethane,chloroform, benzene or acetone, or according to the method described inTetrahedron 28, 3009 (1972) from the aldehydes of formula (XI).

The compounds of formula (VI) wherein Z is >CH₂ may be prepared, forexample, by cyclizing a compound of formula (XVI) ##STR22## where R, R₁,n, n₁, R₃ and X have the meanings reported above, using approximatelythe same reaction conditions reported above

The compounds of formula (VI) wherein Z is >C═O may be obtained, forexample, by reacting a compound of formula (XVII) ##STR23## where R, R₁,n, n₁ are as defined above and each of the groups R_(a), which may beidentical or different, is C₁ -C₆ alkyl, preferably methyl or ethyl,with an amine of formula R₃ --NH₂ where R₃ has the meanings reportedabove. The reaction is preferably carried out under pressure in asuitable solvent, e.g. a C₁ -C₆ aliphatic alcohol, for example ethylalcohol, at temperatures varying from about 50° to about 150° C. If thereaction is performed using controlled temperature, time andstoichiometry conditions, then a compound of formula (XVII) where one ofthe groups --COOR_(a) is replaced by a group --CONHR₃ is obtained, fromwhich a compound of formula (VI) may be obtained by boiling, e.g. inacetic acid, or by treatment with a strong base, e.g. NaH, in a suitablesolvent, e.g. dimethylformamide or dimethylsulphoxide. Compounds (VI)may also be obtained from the imides corresponding to the amides offormula (XIV) by the same procedure described above for the preparationof compounds (III) from compounds (XIV).

The compounds of formula (VII) where one of the groups R_(b) and R_(c)is hydrogen and the other is --C.tbd.N may be prepared by known methods,for example by reacting a compound of formula (II) wherein R₂ ishydrogen with a C₁ -C₆ alkyl-halo-acetate, for exampleethylbromoacetate, in the presence of a base, e.g. an alkaline carbonateor bicarbonate, e.g. K₂ CO₃, in an anhydrous solvent such as, forexample, dimethylacetamide, diemthylformamide, dimethylsulphoxide andsimilar at temperatures varying, e.g., from room temperature to about80° C.

The compounds of formula (VII) where R_(b) and R_(c), taken together,form the radical ═CH--NO₂ may be obtained, by analogous way, startingfrom a compound of formula (IV) wherein R₂ is a cation, e.g. an alkalinecation, for example sodium, by reaction with a C₁ -C₆alkyl-halo-acetate, preferably ethylbromoacetate, at temperaturesranging from about 0° C. to about 50° C. in an anhydrous solvent suchas, for example, tetrahydrofuran, dioxane or one of the solventshereabove mentioned.

The compounds of formula (VIII) may be prepared, for instance, from thecompounds of formula (IX) as described, e.g. in Ind. J. Chem. 13, 462(1975), or by reducing a compound of formula (XVI) using the knownmethods of the organic chemistry, for example with BH₃ under nitrogenatmosphere at a temperature between about -10° C. and about 0° C. in aninert anhydrous solvent such as, e.g., tetrahydrofuran or an aliphaticether, e.g. diethylether.

The compounds of formula (IX) where R₃ is hydrogen may be prepared bythe methods indicated previously at the points (a), (b) and (c). Thecompounds of formula (IX) where R₃ is different from hydrogen may beobtained alkylating by known methods, e.g. those reported above for thealkylation of the amines, the compounds of formula (IX) where R₃ ishydrogen, or reducing the compounds of formula (III) wherein R₂ ishydrogen as described above.

The compounds of formula (X) are known compounds or, respectively, maybe prepared by known methods.

The aldehydes of formula (XI) may be obtained by the usual methods forpreparing the aldehydes described in the Organic Chemistry, e.g.oxidizing the corresponding primary alcohols, e.g. by treatment with 99%phosphoric acid in the presence of dicyclohexylcarbodiimide byconventional way, or reducing the corresponding acid chlorides accordingto known procedures. This reduction may be performed, e.g., with a mixedhydride, in particular with tri-tert.butoxy lithium aluminium hydride,at temperatures varying between about -70° C. and about -50° C. in ananhydrous solvent, for example diethylenglycol dimethylether,tetrahydrofuran, diethylether and similar. The acid chlorides mentionedabove may be in turn obtained from the corresponding carboxylic acids,that is α-phenoxyphenyl acetic acids, by the classic methods of theorganic chemistry, for example by treatment with thionyl chloride orwith oxalyl chloride in the absence of solvents or in an organicanhydrous solvent, e.g. benzene, toluene and similar, according to knownprocedures.

The compounds of formula (XII), as well as the reactive derivatives ofthe compounds of formula (XII), may be prepared by known methods; inparticular the C₁ -C₆ alkyl esters of the compounds of formula (XII)where R₂ is hydrogen may be obtained, e.g., reacting a compound offormula (XVIII) ##STR24## where R₁, n₁ and R_(a) have the meaningsreported above, with a compound of formula (XIX) ##STR25## where R and nare as defined above, in the presence of a catalytic amount of a basewhich may be, for instance, an alkaline, e.g. sodium, carbonate or astrong base or the salt of the phenol of formula (XIX), either in theabsence of solvents or in an appropriate solvent, e.g. a C₁ -C₆aliphatic alcohol, preferably ethyl alcohol, or dimethylformamide.

The compounds of formula (XIII) may be prepared, for example, bytreating a reactive derivative of a compound of formula (XII) where R₂is hydrogen, preferably a C₁ -C₆ alkyl ester thereof, with a compound offormula HO--CH₂ --NHR₃, wherein R₃ is as defined above and, if desired,converting the compound of formula (XIII) where X is --OH, so obtained,into the corresponding halide or reactive ester by known methods.

The compounds of formula (XIV) may be prepared by known methods, forexample by treating a compound of formula (XX) ##STR26## where R₁, n₁and R₃ are as defined above, with the appropriate phenyl chloroformiatein the presence of a base, e.g. pyridine, by standard procedures.

The compounds of formula (XVI) may be obtained, for example, by reactinga compound of formula (IX) with a compound of formula ##STR27## where Xhas the meanings reported above and Y' is halogen, preferably chlorine,by known methods, for instance in an organic or aqueous-organic solvent,e.g. methylenchloride or methylenchloride and water, in presence of abase, e.g. NaOH.

The compounds of formula (XVII) may be prepared from a compound offormula (XII) where R₂ is hydrogen and the carboxy group is esterifiedas a C₁ -C₆ alkyl ester, by treatment with a C₁ -C₆ alkyl-halo-acetate,preferably ethylbromoacetate, in presence of a base, e.g. K₂ CO₃ or Na₂CO₃, in an appropriate solvent, e.g. dimethylformamide, by knownmethods.

The compounds of formula (XV), (XVIII), (XIX) and (XX) are knowncompounds or, respectively, may be prepared by known methods from knowncompounds. In particular, a compound of formula (XX) where R₁ ishydrogen, and n₁ is 1 may be obtained reacting the desiredmorpholin-3-one derivative with benzaldehyde in presence of a strongbase, for example butyl lithium, in an anhydrous solvent, for exampletetrahydrofuran, at a temperature varying between about -70° C. andabout -50° C. By analogous way the compounds of formula (XX) where R₁ isdifferent from hydrogen may be prepared.

The compounds of the present invention are active on the central nervoussystem, in particular, as antidepressant agents.

The antidepressant activity was evaluated in mice on the basis of theprevention of reserpine-induced blepharospasm and hypothermia. Reserpinewas administered endoperitoneally at a dosage of 2.5 mg/kg, and thetested compounds were orally administered 30 minutes before theadministration of reserpine. Recording of blepharospasm [evaluated inscores according to the technique described by Rubin B. et al. in J.Pharmacol., 120, 125 (1957)] and measurement of body temperature (bymeans of a rectal thermocouple) were taken an hour, and respectivelyfour hours after the administration of reserpine.

The compounds of the present invention are preferably administeredorally, although they can be administered also in other conventionalways, for example, by injection or by rectal way.

The dosage suitable for the oral administration to adult humans of thecompounds of the invention, is preferably 5-30 mg pro dose 2-4 times aday.

The pharmaceutical compositions containing the compounds of theinvention are prepared according to conventional methods with the usualingredients.

Thus, for oral administration, the pharmaceutical compositionscontaining the compounds of the invention are preferably tablets, pillsor capsules which contain the active substance together with diluents,such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol,cellulose; lubricants, for instance, silica, talc, stearic acid,magnesium or calcium stearate and/or polyethylene glycols; or they mayalso contain binders, such as, for example, starches, gelatine,methylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone;disintegrating agents, such as, for instance, starches, alginic acid,alginates; effervescing mixtures; dyestuffs; sweeteners; wetting agents,such as, for instance, lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

Also the other pharmaceutical formulations containing the compounds ofthe invention may be prepared by known methods and they can be, forexample, syrups or drops for the oral administration, sterile solutionsfor injection, or suppositories.

In the following examples, THF, DMF, DMA, MCPBA and diglyme referrespectively to tetrahydrofuran, dimethylformamide, dimethylacetamide,m-chloro-perbenzoic acid and diethylenglycol dimethylether. Very broadmelting points generally refer to mixtures of diastereoisomers.

The following examples illustrate but do not in any way limit thepresent invention.

EXAMPLE 1

To a well stirred mixture of2-hydroxy-3-(3,4-methylendioxyphenoxy)-3-phenyl-propylamine (2.87 g) inCHCl₃ (28 ml), NaOH 2 N (8.3 ml) was added. The mixture was cooled to 0°C. and, at this temperature, over about 30', a solution of ethylchloroformiate (1.58 ml) in CHCl₃ (2 ml) was dropped. The stirring wascontinued for 15', the organic phase was separated and the aqueous phasewas extracted with CHCl₃. The combined organic extracts were washed withwater, dried over Na₂ SO₄ and evaporated to dryness to giveN-ethoxy-carbonyl-2-hydroxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine(oil; yield 94.8%).

This oil was dissolved in anhydrous diethylether (100 ml) and addeddropwise, under stirring, to a mixture of LiAlH₄ (1.02 g) in anhydrousdiethylether (25 ml).

The mixture was stirred at room temperature for 20 hours, cooled anddecomposed with water (1 ml), 20% NaOH (0.75 ml) and water (3 ml). Theresidue was filtered off and washed with diethylether. The ether wasdried over Na₂ SO₄ and evaporated to dryness to giveN-methyl-2-hydroxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine, g2.35; m.p. 100°-122° C. (yield 85%). Analogously, the followingcompounds were prepared:

N-methyl-2-hydroxy-3-phenoxy-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine HCl m.p.94°-112° C.

N-methyl-2-hydroxy-3-(3-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(4-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(4-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(2-chloro-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(4-chloro)-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-3-phenyl-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(4-methoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(4-ethoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-trifluoromethyl-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(4-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(4-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-hydroxy-3-phenoxy-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-hydroxy-3-(2-ethoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine.

EXAMPLE 2

To a stirred solution ofN-ethoxycarbonyl-2-hydroxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine(3.59 g) in anhydrous dimethylformamide (30 ml) and methyliodide (6.23ml) cooled to 0°-5° C., 55% NaH (4.36 g) was added. Stirring and coolingwere continued for 1 hour and 30'.

The reaction mixture was cautiously decomposed with water then dilutedwith plentiful water and extracted with ethyl acetate; the organic phasewas washed with water, dried over Na₂ SO₄ and evaporated to dryness.

The residue was purified by dissolving it in methanol and filtering offthe insoluble material. The filtrate was evaporated to dryness to giveN-methyl-N-ethoxycarbonyl-2-methoxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine,3.1 g; oil; yield 80.2%.

The obtained oil was heated to the reflux temperature, under stirring,with 10% methanolic KOH (44.8 ml). After 48 hours, the reaction mixturewas concentrated to dryness then n-propyl alcohol was added toreintegrate the original volume. The whole was boiled for 20 hours andevaporated to dryness; the residue was taken up with water and extractedwith diethylether. The ether was extracted with 3% HCl, the acidicextract was basified with 20% NaOH and re-extracted with diethylether.The organic phase was washed with water, dried over Na₂ SO₄ andevaporated to dryness to giveN-methyl-2-methoxy-3-(3,4-methylendioxy-phenoxy)-3-phenyl-propylamine,2.05 g; oil; yield 81.3%. HCl m.p. 142°-145° C.

Analogously the following compounds were prepared:

N-methyl-2-methoxy-3-phenoxy-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine. HCl m.p.115°-120° C.

N-methyl-2-methoxy-3-(3-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(4-methoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(4-ethoxy-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(2-chloro-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(4-chloro-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-(4-trifluoromethyl-phenoxy)-3-phenyl-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(2-methoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-(3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(4-methoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(4-ethoxy-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-trifluoromethyl-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-(4-trifluoromethyl-phenoxy)-3-(4-ethoxy-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(2-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(3-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(4-chloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(4-methoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-(4-ethoxy-phenoxy)-3-(4-trifluoromethyl-phenyl)-propylamine;

N-methyl-2-methoxy-3-phenoxy-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-methoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine;

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-(3,4-dichloro-phenyl)-propylamine.

EXAMPLE 3

Under an atmosphere of nitrogen to 15.7 g of2-hydroxy-3-(2-chloro-phenyl)-3-(2-methoxy-phenoxy)-propionitrile in 110ml of anhydrous THF there was added at 15° C. 46.2 ml of a 1.35 Msolution of diborane in tetrahydrofuran. Stirring was continued at roomtemperature for 16 hours. A small quantity of ethanol was added and thewhole was evaporated to dryness. The residue was dissolved in ethylether, extracted with 3% HCl, made alkaline with 20% NaOH, re-extractedwith ethyl ether. After washing with water, drying over Na₂ SO₄,filtration and evaporation to dryness, there was obtained 12.45 g of2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-chlorophenyl)-propylamine. Yield78%.

All the primary amines useful for the preparation of the N-methylderivatives mentioned in the examples 1 and 2 were analogously prepared.

EXAMPLE 4

To a mixture of 31.07 g of LiAlH₄ in 1500 ml of anhydrous ethyl ether asolution of 156.6 g of2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propionitrile in 1200 ml ofanhydrous ethyl ether and 150 ml of anhydrous THF, was added dropwisewithout cooling. The whole was stirred for 16 hours at room temperatureand then refluxed for 1 hour, cooled to 0° C. and decomposed with 31 mlof H₂ O, 31 ml of 15% NaOH, 93 ml of H₂ O. The insoluble matter wasfiltered and well washed with ethyl acetate under heating.

After evaporating the solvent the residue was dissolved in 600 ml ofethyl ether; the whole was extracted with 3% HCl, made alkaline with 20%NaOH and re-extracted with ether. After normal processing there wasobtained 86.2 g of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine,melting point 80°-110° C. (Yield 54.4%), as a mixture ofdiastereoisomers in a ratio of approximately 1:1. The mixture wasseparated by chromatography on silica gel (phase: CHCl₃ /CH₃ OH/32% NH₄OH--150/50/2) in this way obtaining two distinct diastereoisomershaving, respectively, melting point of 126°-129° C. (diastereoisomerwith R_(f) <) and of 105°-110° C. (diastereoisomer with R_(f) >).

All the primary amines useful for the preparation of the N-methylderivatives mentioned in the Examples 1 and 2, except those containingchloro, were similarly prepared.

EXAMPLE 5

2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitriledissolved in 25 ml of anhydrous DMF and 7.1 g of methyl iodide werestirred at 0° C. Addition was made, in portions, of 2.18 g of 55% NaH.After the addition, the whole was stirred at 0°-5° C. for 1 and a halfhours. Under an atmosphere of nitrogen the whole was then decomposedcautiously with water, diluted with plentiful water, extracted withethyl acetate and washed with water. The organic phase was dried overNa₂ SO₄ and evaporated to dryness, in this way obtaining 1.95 g of2-methoxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as an oil.Yield=69%.

Analogously, all the 2-methoxy-propionitrile derivatives useful for thepreparation of the 2-methoxy-propylamines listed in Example 2 andobtained according to the reduction of Example 3, were prepared.

EXAMPLE 6

150 g of α-(2-methoxy-phenoxy)-phenyl acetaldehyde dissolved inapproximately 1800 ml of diglyme was stirred with 176.5 g of sodiummetabisulphite in 500 ml of water and 200 ml of ethanol at 50° C. for 16hours. The whole was cooled to room temperature and addition was made of44.4 g of potassium cyanide in 200 ml of water. The whole was stirred at90° C. (external temperature) for 5 hours, concentrated to approximately800 ml and poured into water: extraction was performed with 4×750 ml ofethyl ether and the whole washed with water, dried over Na₂ SO₄ andevaporated to dryness to obtain 156.5 g of2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as a viscous oil.Yield=94%.

Analogously, all the 2-hydroxy-propionitrile derivatives useful for thepreparation of the 2-hydroxy-propylamines mentioned in Examples 3 and 4were prepared.

EXAMPLE 7

171 g of the chloride of α-(2-methoxy-phenoxy)-phenylacetic acid wasdissolved in 1000 ml of anhydrous diglyme under stirring. At atemperature of between -60° C. and -65° C. there was added dropwise overtwo and a half hours 173 g of tris-tertbutoxy lithium aluminium hydridedissolved in 800 ml of anhydrous diglyme. When the addition wascomplete, the temperature was maintained at -60° C. for 30 minutes. Thetemperature was then allowed to rise to -40° C. and the mixture wasdecomposed with 152 g of ammonium sulphate in 228 ml of water. The wholewas diluted with 2000 ml of ethyl ether and Celite was added. The wholewas filtered at approximately 0° C. and then the residue was washedthoroughly with ethyl ether. The ether was concentrated under vacuum atbelow 30° C., to obtain a solution of diglyme containingα-(2-methoxy-phenoxy)-phenyl acetaldehyde in quantitative yield: thissolution was used as such, to obtain the propionitrile of the Example 6.

Analogously, all the aldehydes useful for the preparation of thepropionitrile derivatives obtained according to Example 6 were prepared.

EXAMPLE 8

0.47 g of α-(3-methoxy-phenoxy)-phenylacetic acid was dissolved in 20 mlof anhydrous benzene. At room temperature there was added dropwise 1.9ml of oxalyl chloride diluted with 7 ml of anhydrous benzene. The wholewas refluxed for 5 hours, then evaporated to dryness taking up twicewith anhydrous benzene and again concentrating to dryness. There was inthis way obtained the chloride of α-(3-methoxy-phenoxy)-phenylaceticacid with a quantitative yield of (0.50 g), which was used as such forthe reduction to aldehyde reported in Example 7.

Analogously, all the acid chlorides useful for the preparation of thealdehydes mentioned in Example 7 were prepared.

EXAMPLE 9

160 g of α-(2-methoxy-phenoxy)-phenylacetic acid was mixed with 500 mlof thionyl chloride at room temperature. After 20 hours the reaction wascomplete. The whole was evaporated to dryness, taking up the residuetwice with anhydrous benzene and again evaporating to dryness. There wasin this way obtained with quantitative yield (171 g) the chloride ofα-(2-methoxy-phenoxy)-phenylacetic acid which was used as such for thereduction to aldehyde reported in Example 7.

Analogously, the acid chlorides useful for the preparation of thealdehydes mentioned in Example 7 were prepared. The phenylacetic acidsused as starting material for the preparation of the acid chloridesindicated in this example and Example 8 were known compounds which canbe prepared with known methods, as for example described in Bull. Soc.Chem. Fr. 1956, 776.

EXAMPLE 10

50.3 g of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionamidedissolved in 1000 ml of anhydrous THF was reduced to amine by slowlyadding at 8° C. 340 ml of a molar solution of diborane in THF. The wholewas refluxed for 4 hours, cooled to room temperature, the excess ofdiborane was decomposed with MeOH and then, again at room temperature,dropwise addition was made of 400 ml of an ethereal solution of HCl. Thewhole was left to stand for 16 hours and then evaporated to dryness atreduced pressure, taken up with CH₂ Cl₂ and washed once with an aqueoussolution of sodium bicarbonate. The organic phase was then washedseveral times with a saturated aqueous solution of NaCl, dried withsodium sulphate and evaporated to dryness. The dark oil forming theresidue was dissolved in 800 ml of ethyl ether and alcoholichydrochloric acid (18% solution in ETOH) was added; there was obtained50.9 g of N-methyl-2-hydroxy-3-(2-nitro-phenoxy)-3-phenyl-propylamine,hydrochloride, m.p. 197°-203° C. (yield 94%).

IR νmax (KBr) 1525 cm⁻¹ (NO₂). 2700 cm⁻¹ (NH₂ ⁺).

Analogously, all the compounds listed in Examples 1 and 2 were prepared.

EXAMPLE 11

40 g of ethyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate in 1liter of 95° ethyl alcohol and 250 ml of 35% methylamine was heated in astopped vessel at 40°-50° C. for 24 hours. The whole was evaporated todryness under vacuum, taken up with 200 ml of absolute ethyl alcohol,again evaporated to dryness and the residue crystallized fromisopropanol. There was in this way obtained 36 g (94.2%) ofN-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionamide, meltingpoint 162°-163° C.

I.R. νmax (nujol) 1640 cm⁻¹ (CON). 3300 cm⁻¹ (OH--broad band). 3400 cm⁻¹(narrow, intense band).

Analogously, the propionamides useful for the preparation of thepropylamines obtained according to Example 10 were prepared.

EXAMPLE 12

66 g of trans ethyl glycidate and 48 g of o-nitrophenol were dissolvedin 1 liter of absolute ethyl alcohol to which 36 g of anhydrous Na₂ CO₃was added. The whole was refluxed under stirring for 48 hours, a further24 g of o-nitrophenol was added and the whole was refluxed for another36 hours, after which it was evaporated to dryness under vacuum, dilutedwith water and extracted with ethyl acetate which was then washed with 2N NaOH until the excess phenol was wholly extracted. The whole was thenwashed with water to neutrality, dried over Na₂ SO₄ and evaporated todryness. The residue was crystallized from Et₂ O to obtain 67 g (60%) ofethyl 2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate, m.p. 129°-131°C.

I.R. νmax (nujol) 1525 cm⁻¹ (NO₂). 3300 cm⁻¹ (OH broad band). 1740 cm⁻¹##STR28##

Analogously, all the 2-hydroxy-propionates useful for the synthesis ofthe 2-hydroxy-propionamides obtained according to Example 11 (includingthe diastereoisomers obtained starting from the cis glicidates) wereprepared.

EXAMPLE 13

To 2 g of ethyl 2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionatedissolved in 30 ml of anhydrous dimethylformamide, CH₃ I (0.78 ml) wasadded at 3° C., then, in two additions, at the same temperature, NaH 50%(0.3 g) was added too. The whole was stirred at 3° C. for one hour andat room temperature for one hour, after which it was poured into 300 mlof water, extracted with ethyl ether which, after washing with NaClsaturated water and dehydration with sodium sulphate, was evaporated todryness under reduced pressure. There was obtained 2 g (96%) of ethyl2-methoxy-3-phenyl-3-(2-nitro-phenoxy)-propionate as an oil.

I.R. νmax (film) 1740 cm⁻¹ ##STR29## 1525 cm⁻¹ (NO₂).

N.M.R.: ppm (CDCl₃): 3.24 (3H).

Analogously, all the 2-methoxy-propionates useful for the preparation ofthe 2-methoxy-propionamides obtained according to Example 11 wereprepared.

EXAMPLE 14

6.9 g of ethyl 3-phenyl-3-(2-nitro-phenoxy)-2-methoxy-propionate,dissolved in 150 ml of absolute ethanol, was hydrogenated (5%Palladium-charcoal) at ambient pressure and temperature.

The reaction was complete within 30 minutes. The catalyst was filteredand the solvent eliminated at reduced pressure. To the remaining oil,taken up with a small quantity of ethanol, there was added 4 ml of 18%HCl in ethanol. By diluting with ethyl ether there was obtained ethyl3-(2-aminophenoxy)-3-phenyl-2-methoxy-propionate hydrochloride.

I.R. νmax (KBr) 2850 cm⁻¹ (ArNH₃ ⁺). 1740 cm⁻¹ ##STR30##

N.M.R.: ppm (DMSO-d₆) 3.24 (s, 3H); 4.05 (q, 2H); 1.21 (t, 3H).

EXAMPLE 15

To a solution of 8 g of ethyl3-(2-amino-phenoxy)-3-phenyl-2-methoxy-propionate, dissolved in 23% HCl(11.6 ml) at 4°-5° C., water (30 ml) was added and, always undercooling, a solution of NaNO₂ (1.73 g) dissolved in water (30 ml) wasslowly dropped. The solution was stirred at room temperature for 30minutes and then heated at 50° C. for 15 minutes; evolution of N₂ wasnoted. After extraction with CH₂ Cl₂ and appropriate washings, the CH₂Cl₂ was evaporated to dryness so obtaining an oil, which was separatedby column chromatography to give 4.0 g of ethyl3-(2-hydroxy-phenoxy)-3-phenyl-2-methoxy-propionate (50%).

I.R. νmax (CHCl₃) 3500 cm⁻¹ (OH dimer--broad band). 1740 cm⁻¹ ##STR31##

EXAMPLE 16

To a solution of 9.5 g ofethyl-3-(2-hydroxy-phenoxy)-3-phenyl-2-methoxy-propionate in 130 ml ofanhydrous dimethylformamide there was added 4.8 ml of anhydrouspotassium carbonate and then, under stirring, dropwise addition was madeof 2.2 ml of CH₃ I in 15 ml of dimethylformamide. After four and a halfhours the mixture was poured into 1 liter of water, then extracted twicewith ethyl acetate. The extracts were combined, washed with water anddehydrated and then concentrated at reduced pressure. Chromatography onsilica gel was performed to obtain 8.6 g of ethyl3-phenyl-3-(2-methoxy-phenoxy)-2-methoxy propionate. Yield=86.8%.

I.R. νmax (film) 2815 cm⁻¹ (OCH₃). 1738 cm⁻¹ ##STR32##

EXAMPLE 17

To a solution of 2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine(11.6 g) and triethylamine (3.5 g) in benzene (100 ml) a solution of CH₃I (5.5 g) in benzene (20 ml) was added dropwise at room temperature over1 hour. Stirring was continued at room temperature for 20 hours, themixture was filtered and the solvent was evaporated to dryness soobtaining an oil which was separated on silica gel column to give4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (7 g;yield 57%).

Analgously, the following 4-methyl-morpholine derivatives were prepared:

4-methyl-2-(α-phenoxy-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine. HCl m.p. 67°-90°C.;

4-methyl-2-[α-(3-methoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(4-methoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(4-ethoxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(2-chloro-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(4-chloro-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(4-trifluoromethyl-phenoxy)-benzyl]-morpholine;

4-methyl-2-[α-(3,4-methylendioxy-phenoxy)-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-2-methoxy-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-4-ethoxy-benzyl)-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-[α-(4-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-[α-(4-trifluoromethyl-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-[α-(4-chloro-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-[α-(4-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-2-chloro-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-2-chloro-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-3-chloro-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-3chloro-benzyl ]-morpholine;

4-methyl-2-(α-phenoxy-4-chloro-benzyl)-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-[α-(4-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-[α-(4-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-[α-(4-chloro-phenoxy)-4-chloro-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-4-trifluoromethyl-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-[α-(4-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-[α-(4-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-[α-(4-chloro-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-methyl-2-(α-phenoxy-3,4-dichloro-benzyl)-morpholine;

4-methyl-2-[α-(2-methoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

4-methyl-2-[α-(2-ethoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine.

EXAMPLE 18

To a solution of 2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine(7.35 g) in CHCl₃ (50 ml), 2 N NaOH (18.2 ml) was added; the mixture wascooled to 0° C. and ethyl chloroformiate (3.5 ml) was dropped over 30minutes. Stirring and cooling at 0° C. was maintained for 1 hour; theorganic phase was separated, washed with water and dried over anhydrousCaCl₂. The evaporation to dryness of the solvent gave a colourless oilwhich was dissolved in diethyl ether (100 ml) and added, at roomtemperature, to a suspension of LiAlH₄ (2.5 g) in anhydrous diethylether (200 ml). The mixture was stirred at room temperature for 20hours; water (2.5 ml), 15% NaOH (2.5 ml) and water (7.5 ml) were added.After filtration, the ethereal layer was separated and the aqueous phasewas extracted with diethyl ether. The combined organic phases werewashed with water and dried over anhydrous Na₂ SO₄. After evaporation todryness of the solvent,4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine wasobtained as oil (6.25 g; yield 82%).

Analogously, all the 4-methyl-morpholine derivatives of the example 17were prepared.

EXAMPLE 19

To a well stirred mixture of2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine (2 g) in glacialacetic acid (5.2 ml), acetone (12 ml) and water (8 ml), NaBH₄ (6.024 g)was added over 1 hour maintaining the temperature near 0° C. Then moreacetone (12 ml) and NaBH₄ (3 g) were added; the temperature was allowedto rise to room temperature and after 30 hours the reaction mixture waspoured into a solution of NaHCO₃ in water, then extracted with diethylether. The ethereal extracts were washed with water, dried over Na₂ SO₄and evaporated to dryness to give4-isopropyl-2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine (1.85g; yield 82.3%) .HCl m.p. 200°-240° C.

Analogously, the following 4-isopropyl-morpholine derivatives wereprepared:

4-isopropyl-2-(α-phenoxy-benzyl)-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine.HCl m.p.196°-203° C;

4-isopropyl-2-[α-(3-methoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(4-methoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(4-ethoxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(2-chloro-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(4-chloro-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(4-trifluoromethyl-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-[α-(3,4-methylendioxy-phenoxy)-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-2-methoxy-benzyl)-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-4-ethoxy-benzyl)-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-[-60 -(4-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-[α-(4-trifluoromethyl-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-[α-(4-chloro-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-[α-(4-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-2-chloro-benzyl)-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-2-chloro-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-3-chloro-benzyl)-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-3-chloro-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-4-chloro-benzyl)-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(4-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(4-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-[α-(4-chloro-phenoxy)-4-chloro-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-4-trifluoromethyl-benzyl)-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(4-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(4-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-[α-(4-chloro-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

4-isopropyl-2-(α-phenoxy-3,4-dichloro-benzyl)-morpholine;

4-isopropyl-2-[α-(2-methoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

4-isopropyl-2-[α-(2-ethoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine.

EXAMPLE 20

To 33 g of 2-[α-(2-nitro-phenoxy)-benzyl]-morpholin-3-one dissolved in60 ml of anhydrous THF there was added dropwise under stirring 16.7 mlof a 0.9 M solution of BH₃ in THF. The whole was heated at reflux for 3hours and dropwise addition under cold conditions (0°-5° C.) was thenmade of 3 ml of methanol and then of 3 ml of 23% HCl. The solvent wasremoved under reduced pressure. The residue was diluted with H₂ O, madealkaline and extracted with chloroform. The organic extracts were washedto neutrality, dried and evaporated to dryness, to obtain 2 8.6 g of2-[α-(2-nitrophenoxy)-benzyl]-morpholine. Yield 94%.

I.R. ν max (CHCl₃) 3320 cm⁻¹ (N-H). 1525 cm⁻¹ (NO₂).

Analogously, the following compounds were prepared:

2-(α-phenoxy-benzyl)-morpholine.HCl m.p. 199°-202° C.;

2-[α-(2-methoxy-phenoxy)-benzyl]morpholine.HCl m.p. 14020 -170° C.;

2-[α-(3-methoxy-phenoxy)-benzyl]-morpholine, n_(D) 1.5762.

2[α-(4-methoxy-phenoxy)-benzyl]-morpholine;

2[α-(2-ethoxy-phenoxy)-benzyl]-morpholine, one diastereoisomer m.p.170°-1° C;

2-[α-(4-ethoxy-phenoxy)-benzyl]-morpholine;

2-[α-(2-chloro-phenoxy)-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-benzyl]-morpholine;

2-[α-(4-trifluoromethyl-phenoxy)-benzyl]-morpholine;

2-[α-(3,4l -methilendioxy-phenoxy)-benzyl]-morpholine.HCl m.p. 82°-130°C.;

2-(α-phenoxy-2-methoxy-benzyl)-morpholine;

2-[α-(2-methoxy-phenoxy)-2-methoxy-benzyl]-morpholine, n_(D) 1.5672;

2-[α-(2-ethoxy-phenoxy)-2-methoxy-benzyl]-morpholine;

2-(α-phenoxy-4-ethoxy-benzyl)-morpholine;

2-[α-(2-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(4-ethoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(4-trifluoromethyl-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-[α-(4-methoxy-phenoxy)-4-ethoxy-benzyl]-morpholine;

2-(α-phenoxy-2-chloro-benzyl)-morpholine;

2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine, m.p. 80°-102° C.;

2-[α-(2-ethoxy-phenoxy)-2-chloro-benzyl]-morpholine;

2-(α-phenoxy-3-chloro-benzyl)-morpholine;

2-[α-(2-methoxy-phenoxy)-3-chloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-3-chloro-benzyl]-morpholine;

2-(α-phenoxy-4-chloro-benzyl)-morpholine;

2-[α-(2-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(4-ethoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(4-metoxy-phenoxy)-4-chloro-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-4-chloro-benzyl]-morpholine;

2-(α-phenoxy-4-trifluoromethyl-benzyl)-morpholine;

2-[-60 -(2-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(4-methoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(4-ethoxy-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-[α-(4-chloro-phenoxy)-4-trifluoromethyl-benzyl]-morpholine;

2-(α-phenoxy-3,4-dichloro-benzyl)-morpholine;

2-[α-(2-methoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

2-[α-(2-ethoxy-phenoxy)-3,4-dichloro-benzyl]-morpholine;

as well as all the compounds mentioned in Examples 17 and 19.

EXAMPLE 21

To a solution of 4.24 g ofN-(2-mesyloxyethyl)-3-phenyl-2-hydroxy-3-(2-nitro-phenoxy)-propionamidein 150 ml of DMF there was added 1.38 g of potassium carbonate. Thestirred mixture was heated at 50° C. for 5 hours, then poured into waterand extracted with ethyl acetate. The dehydrated organic extracts wereevaporated to dryness and the residue was chromatographed on silica gel,to obtain 1.27 g of 2-[α-(2-nitro-phenoxy)-benzyl]-morpholin-3-one.Yield 38.6%.

I.R. ν max (nujol) 3450 cm⁻¹ (NH). 1670 cm⁻¹ (CONH). 1525 cm⁻¹ (NO₂).

Analogously, the morpholin-3-one derivatives useful for the preparationof the compounds mentioned in the Examples 17, 19 and 20 were prepared.

EXAMPLE 22

To 5.2 g ofN-(2-hydroxy-ethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionamidedissolved in 200 ml of anhydrous THF there was added 2.4 ml oftriethylamine. The solution was cooled to -10° C. and, under stirring,slow dropwise addition was made of a solution of 1.83 f of mesylchloride in 30 ml of THF. After 45 minutes at -10° C. the temperaturewas allowed to rise to room temperature. The solution was concentratedto a small volume at reduced pressure. The residue was poured intowater. The mixture was extracted with chloroform, the extracts washed toneutrality with water and then dried over sodium sulphate.

The solvent was removed at reduced pressure and the residue wascrystallized from 95° ethanol, to obtain 4.86 g ofN-(2-mesyloxy-ethyl)-3-phenyl-2-hydroxy-3-(2-nitrohenoxy)-propionamide,m.p. 122°-125° C. (yield 76.5%).

I.R. ν max (KBr) 3500 cm⁻¹ (OH-- broad band). 3450 cm⁻¹ (NH). 1650 cm⁻¹(CONH). 1525 cm⁻¹ (NO₂). 1350 cm⁻¹ (SO₂). 1180 cm⁻¹ (SO₂).

Analogously, the N-(2-mesyloxy-ethyl)-propionamides useful for thepreparation of the compounds mentioned in Example 21 were prepared.

EXAMPLE 23

3 g of ethyl-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionate wasrefluxed with 5.4 ml of ethanolamine in 50 ml of anhydrous ethanol for20 hours. The solvent was removed under reduced pressure, the residuewas taken up with water and the solid collected by filtration. Aftercrystallization from ethyl acetate, 1.8 g ofN-(2-hydroxyethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionamidewas obtained, m.p. 166°-188° C. Yield 58%.

I.R. ν max (nujol) 3400 cm⁻¹ (OH, NH-- broad band). 1650 cm⁻¹ (CONH).1525 cm⁻¹ (NO₂).

Analogously, the N-(2-hydroxy-ethyl)-propionamides useful for thepreparation of the compounds mentioned in Example 22 were prepared.

EXAMPLE 24

A mixture of 0.9 g of 2-(α-phenoxy-carbonyloxy-benzyl)-morpholin-3-onein 2.5 ml of HMPT was heated to 140° C. After 1 hour the reaction wascomplete. The whole was diluted with water and extracted with ethylacetate. The organic extracts were washed with water, dried over Na₂SO₄, filtered and concentrated to dryness, to obtain2-(α-phenoxy-benzyl)-morpholin-3-one. There were similarly prepared allthe morpholin-2-one derivatives necessary for the preparation of theExample 20.

EXAMPLE 25

To 0.6 g 2-(α-hydroxy-benzyl)-morpholin-3-one dissolved in 5 ml ofanhydrous pyridine at 0° C. there was added dropwise 0.5 g of phenylchloroformate. The whole was stirred at room temperature for 12 hours.Addition was made of 30 ml of CH₂ Cl₂, washing was performed with 5% HClthen with 5% NaOH and finally with water. The organic phase was driedover Na₂ SO₄. The whole was filtered and evaporated to dryness to obtain2-(α-phenoxy-carbonyloxy-benzyl)-morpholin-3-one. Yield 95% Similarly,all the analogous intermediates useful as starting materials for thepreparation of the compounds of Example 24 were prepared.

EXAMPLE 26

Under an atmosphere of nitrogen and in a anhydrous apparatus a mixtureof 2.02 g of morpholin-3-one in 60 ml of anhydrous THF was stirred.Dropwise addition was made at room temperature of 26.7 ml of 15% butyllithium in hexane over 45 minutes. After 2.5 hours of stirring at roomtemperature the whole was cooled to -62° C. and a solution of 2.02 ml offreshly distilled benzaldehyde in 10 ml of anhydrous THF was added, over45 minutes. The mixture was kept at -62° C. for 3 hours, allowed to riseto room temperature and kept at this temperature for a further 16 hours.A little water was added and the whole was evaporated to dryness. Theresidue was taken up with a dilute solution of NaHCO₃, extracted withethyl acetate and washed with H₂ O. The solution was dried over Na₂ SO₄,filtered and evaporated to dryness. The solid residue was ground with 40ml of ethyl ether and filtered, to obtain 2.4 g of2-(α-hydroxy-benzyl)-morpholin-3-one which was crystallized from ethylacetate, melting point 130°-140° C. Yield 58.0%.

I.R. ν max (CHCl₃) 3400 cm⁻¹ (OH-- broad band). 3300-3200 cm⁻¹ (NH).1660 cm⁻¹ (CO).

Analogously, all the intermediates useful as starting materials for thepreparation of the compounds of Example 25 were prepared.

EXAMPLE 27

To a suspension of 0.55 g of LiAlH₄ in 18 ml of anhydroustetrahydrofuran there was added dropwise at 30° C. over 4 hours 1 g of2-hydroxy-1-nitro-3-phenyl-3-(2-methoxy-phenoxy)-propane sodium salt in70 ml of anhydrous tetrahydrofuran. After the addition, the mixture wascooled and decomposed with water, 15% NaOH, water. It was then filtered;the solid was washed with tetrahydrofuran and the solvent evaporated todryness. The residue was dissolved in ethyl ether and extracted with 3%HCl, made alkaline with 20% NaOH NaOH and re-extracted with ethyl ether.The organic solution was then washed with water, dried over Na₂ SO₄,filtered and evaporated to dryness. A small quantity of isopropyl etherwas then used to ground it to obtain2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (0.4 g); meltingpoint 84°-110° C. (R=47.2%) as mixture of two diasteroisomers. Themixture was separated by column chromatography on silica gel (phase:CHCl₃ /CH.sub. 3 OH/32% NH₄ OH-150/50/2) to obtain two distinctdiastereoisomers having melting point of 126°-129° C. (diastereoisomerwith Rf<) and 105°-110° C. respectively (diastereoisomer with Rf>).

Analogously, all the primary amines useful for the preparation of theN-methyl-derivatives mentioned in Examples 1 and 2 were prepared.

EXAMPLE 28

(a) To a suspension of 6 g of (2-methoxh-phenoxy)-phenylacetic acid in50 ml of anhydrous tetrahydrofuran there was added 4.52 g ofcarbonyldiimidazole in 65 ml of anhydrous tetrahydrofuran. The whole washeated at reflux for one hour. This solution was used as such in (b).

(b) Under an atmosphere of nitrogen there was washed three times 1.21 gof 55% sodium hydride with anhydrous pentane; the whole was covered with40 ml of anhydrous tetrahydrofuran and dropwise addition was made understirring of 5.7 ml of nitromethane. After fifteen minutes the solution(a) was added to this suspension over 10 minutes. The whole was heatedat reflux for 16 hours, cooled and filtered. The solid, which was thestarting product, was washed with 2×100 ml of CH₂ Cl₂. The solution oftetrahydrofuran was combined with the CH₂ Cl₂ and evaporated to dryness,taken up with hot 99° ethanol, cooled to room temperature and filtered.

There was obtained 4.1 g of2-hydroxy-1-nitro-3-phenyl-3-(2-methoxy-phenoxy)-propene sodium salt,m.p. 120°-135° C. (yield 82%).

I.R. ν max (KBr) 2840 cm⁻¹ (Ar--O--CH₃). 1460-1350 cm⁻¹ (C═C--NO₂).

N.M.R.: ppm (CDCl₃); 7.05 (m, 5H); 6.8 (s, H); 6.6 (m 4H); 5.1 (s, H);3.45 (s, 3H).

Analogously, all the nitro-derivatives useful for the synthesis of the2-hydroxy-propylamines obtained according to Example 27 were prepared.

EXAMPLE 29

A solution of 1 g of2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy-1-nitro-propane sodium salt in 5ml of anhydrous DMA and 0.623 ml of CH₃ I was stirred at 40° C. for 6hours. The whole was poured into water and extracted with ethyl acetate,then washed with water and dried over Na₂ SO₄. After filtration andevaporated to dryness there was obtained 0.90 g of3-phenyl-2-methoxy-3-(2-methoxy-phenoxy)-1-nitro-propene, Yield=92%.

The compounds obtained according to the Example 28 were methylatedsimilarly.

EXAMPLE 30

25.6 g of 3-(2-methoxy-phenoxy)-3-phenyl-propylene-1,2-oxide wasdissolved in 60 ml of benzylamine. The whole was heated at 120° C. for 8hours, the excess of benzylamine was distilled and poured into water;the aqueous solution was extracted 4 times with Et₂ O for a total of1000 ml, washing was effected with plentiful water, and the Et₂ O wasevaporated to dryness to obtain 25.2 g (69.4%) ofN-benzyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine, as aclear colourless oil.

All the primary and secondary 2-hydroxy-propylamines indicated in theExamples 1, 3 and 4 were similarly prepared.

EXAMPLE 31

To a solution of 2.4 g of 3-(2-methoxy-phenoxy)-3-phenyl-propylenedissolved in 20 ml of CH₂ Cl₂, MCPBA (1.9 g) was added at roomtemperature and the whole was kept under stirring for approximately twohours. The m-chlorobenzoic acid was separated by filtration, the organiclayer was washed with water and then with saturated solutions of Na₂ S₂O₅, NaHCO₃ and then again with water. The organic phase was dried overNa₂ SO₄ and evaporated to dryness to obtain 1.6 g (62.5%) of3-(2-methoxy-phenoxy)-3-phenyl-propylene-1,2-oxide. Similarly, all thepropylene-1,2-oxide-derivatives useful for the preparation of the2-hydroxy-propylamines of the Example 30 were prepared.

EXAMPLE 32

To a solution of 5 g of guaiacol sodium salt in 60 ml ofdimethylformamide, 1-phenylallyl-chloride (5.22 g) (J.C.S. 1959, p.2720) was added under a nitrogen atmosphere. The whole was stirred for 4hours at room temperature and for two hours at 50° C., poured into waterand extracted with ethyl ether. After standard working up, followed bychromatographic separation, 3-(2-methoxy-phenoxy)-3-phenyl-propylene(8.1 g; 98%) was obtained.

Analogously, the propylene derivatives useful for the preparation of thecompounds indicated in the Example 31 were prepared.

EXAMPLE 33

Into a solution of 12.3 g of2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one in 350 ml ofanhydrous THF there was slowly added dropwise 77 ml of a molar solutionof BH₃ in THF. After the addition, the mixture was refluxed for 6 hours.The excess of BH₃ was eliminated with MeOH at room temperature, anddropwise addition was then made to the reaction mixture of 50 ml of 23%HCl and stirring carried out for 1 hour at 60° C. The whole wasconcentrated to a small volume and the residue diluted with water,thereafter alkalinizing with NaOH and extracting with CH₂ Cl₂. Afternormal processing and crystallization from isopropyl ether, the2-[α-(2-nitro-phenoxy)-benzyl]-3-methyl-morpholine, m.p. 78°-81° C. (8.1g; 68%) was obtained.

I.R. νmax (CHCl₃) 1525 cm⁻¹ (NO₂).

N.M.R. ppm (CDCl₃) 5.3 (d, H benzylic) 7.4-6.8 (s, 9H aromatic) 2.27 (s,CH₃).

Analogously, the morpholin-5-one derivatives obtained in the examples36, 37, 38 and all the morpholin-5-one derivatives corresponding to thecompounds of the examples 17, 19 and 20 were reduced to thecorresponding morpholines.

EXAMPLE 34

To 24.7 g ofN-chloroacetyl-N-methyl-2-hydroxy-3-phenyl-3-(2-nitrophenoxy)-propylaminedissolved in 300 ml of anhydrous DMF there was added 3.5 g of 50% NaH inmineral oil. The reaction mixture was heated at 50° C. for 3 hours understirring and then allowed to stand for 16 hours, then poured into 2liters of water: a brown solid was separated and was filtered andpurified by mixing with boiling 95% ETOH. There was obtained 18 g (Yield80%) of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one, m.p.192°-195° C.

I.R. νmax (nujol) 1660 cm⁻¹ (CON). 1525 cm⁻¹ (NO₂).

The morpholin-5-one derivatives corresponding to the compounds of theExamples 17, 19 and 20 were similarly prepared.

EXAMPLE 35

To 55 g of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propylaminehydrochloride dissolved in 770 ml of distilled water there was added atroom temperature 185 ml of 2 N NaOH and 200 ml of CH₂ Cl₂. At 0° C.,slow dropwise addition was made to the mixture of 16.7 ml ofchloroacetyl chloride dissolved in 350 ml of anhydrous CH₂ Cl₂. Thesolution was stirred at room temperature for 3 hours. The organic phasewas separated and washed with an aqueous solution of bicarbonate, thenwith a saturated solution of NaCl, then dried and evaporated to dryness.There was obtained 60 g (Yield 97%) ofN-chloroacetyl-N-methyl-3-phenyl-2-hydroxy-3-(2-nitro-phenoxy)-propylamine.

I.R. νmax (CHCl₃) 3500 cm⁻¹ (OH--broad band); 1640 cm⁻¹ (CON); 1525 cm⁻¹(NO₂).

The analogous intermediates useful for the preparation of themorpholin-5-one derivatives of the Example 34 were similarly prepared.

EXAMPLE 36

To a solution of 7 g of2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one in 200 ml ofDMF, 5% Palladium-charcoal (0.7 g) was added and the mixture washydrogenated at 3.5 atmospheres for 0.5 hours. The catalyst was filteredoff, the solution was poured into water and then extracted with ethylacetate. After anhydrification and evaporation to dryness of thesolvent, crystallization from ethyl ether gave2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholin-5-one, m.p. 167°-170°C. (5.3 g; 75.2%).

I.R. νmax (nujol) 3300 cm⁻¹ (NH₂); 1660 cm⁻¹ (CON).

EXAMPLE 37

10 g of 2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholin -5-one wasdissolved at 0° C. in 32 ml of 35% H₂ SO₄. At this temperature slowaddition was made of 2.76 g of NaNO₂ dissolved in 40 ml of H₂ O and themixture was kept under stirring in cold conditions for 20 minutes. Stillat 0° C. there was added 120 g of Cu(NO₃)₂ dissolved in 1000 ml of H₂ Oand 4.2 g of Cu₂ O. After 5 minutes extraction was performed in coldconditions with ethyl acetate; the organic phase was washed toneutrality with a saturated aqueous solution of NaCl, dehydrated withsodium sulphate and evaporated to dryness. There was obtained a yellowoil which was separated by column chromatography on silica gel(phase:ethyl acetate/cyclohexane 2:1). There was obtained 6 g (Yield60%) of 2-[β-(2-hydroxy-phenoxy)-benzyl]-4-methyl-morpholin-5 -one.

I.R. νmax (CHCl₃) 3500 cm⁻¹ (OH); 1660 cm⁻¹ (CON).

EXAMPLE 38

To a solution of 10 g of2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methylmorpholin -5-one in 150 ml ofanhydrous DMF addition was made of 4.8 g of potassium carbonate, andthen dropwise addition was made under stirring of 2.6 ml of bromoethanein 20 ml of DMF. The mixture was heated for 4 hours at 60° C. understirring. The mixture was poured into 1.5 liters of water and extractedwith ethyl acetate. The organic extracts were washed with H₂ O,dehydrated over Na₂ SO₄ and concentrated under reduced pressure. Therewas obtained 8.49 g (Yield 78%) of2-[α-(2-ethoxy-phenoxy)-benzyl]-4-methyl-morpholin -5-one.

I.R. νmax (nujol) 1660 cm⁻¹ (CON).

EXAMPLE 39

A solution of 6.8 g of2-[α-(2-methoxyphenoxy)-benzyl]-4-methylmorpholin-3,5-dione in 40 ml ofanhydrous tetrahydrofuran was added dropwise under stirring to asuspension of lithium aluminium hydride (1.9 g) in 35 ml of THF. Themixture was refluxed under stirring for 6 hours. Dropwise addition wasthen made at 0°-5° C. of 4.1 ml of 23% HCl and the whole was stirred atroom temperature for 2 hours. The suspended solid was filtered andwashed several times with THF. The combined filtrates were evaporated todryness under reduced pressure. The residue was taken up with ethylether and 4 ml of 18% methanolic HCl was added. The amorphoushydrochloride precipitated which was washed several times with freshethyl ether. By filtration there was obtained 5.8 g of2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholine hydrochloride,melting point 67°-90° C. Yield 84%.

I.R. νmax (KBr) 2700 cm⁻¹ (NH⁺) 2815 cm⁻¹ (OCH₃).

All the compounds mentioned in the Examples 17, 19 and 20, except thosecontaining chloro, were similarly prepared. The same reaction describedin Example 39 was carried out with diborane using the procedure ofExample 20; in this way all the compounds mentioned in the Examples 17,19 and 20 were also prepared.

EXAMPLE 40

4 g of ethyl2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)propionatedissolved in 30 ml of ethanol was heated in an autoclave at 150° C. for20 hours with 20 ml of a 10% ethanolic solution of methylamine. Coolingwas allowed to take place and the solvent was removed under reducedpressure. The residue was crystallized from ethanol to obtain 2.26 g of2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholin-3,5-dione. Yield 64%.

I.R. νmax (CHCl₃) 1680 cm⁻¹ (CONCO); 1625 cm⁻¹ (CONCO).

Analogously, the morpholin-3,5-dione derivatives useful as intermediatesfor the preparation of the compounds of Example 39 were prepared.

EXAMPLE 41

A solution of 3.85 g of ethyl 2-hydroxy-3-phenyl-3-(2-methoxyphenoxy)propionate in 35 ml of DMF was heated at 60° C. under stirring for 60hours with 5.34 ml of ethyl bromoacetate and 3.32 g of anhydrouspotassium carbonate. The mixture was then poured into water, extractedwith ethyl acetate and the organic extracts were washed to neutralitywith H₂ O, dehydrated, concentrated under reduced pressure and theresidue chromatographed on silica gel (phase:ethyl acetate/cyclohexane1/1) so obtaining 3.35 g of ethyl2-(ethoxycarbonyl-methyloxy)-3-phenyl-3-(2-methoxy-phenoxy)-propionate.Yield 67%.

I.R. νmax (film) 1815 cm⁻¹ (OCH₃); 1740 cm⁻¹ ##STR33##

Similarly, the analogous intermediates useful for the preparation of thecompounds of Example 40 were prepared.

EXAMPLE 42

To 3.55 g of2-ethoxycarbonyl-methyloxy-3-phenyl-3-(2-methoxyphenoxy)-propionitriledissolved in 40 ml of anhydrous THF and cooled to 10° C. under anatmosphere of nitrogen, slow dropwise addition was made, under stirring,of 15 ml of a molar solution of diborane in tetrahydrofuran. The mixturewas then stirred at room temperature for 16 hours, cooled and decomposedcautiously with 3% HCl. The THF was evaporated and the residue waspurified by dissolving it in 3% HCl, alkalinizing with sodiumbicarbonate and extracting with ethyl ether.

The whole was evaporated to dryness to obtain 2.8 g of an oil which wasdissolved in 30 ml of anhydrous THF. The solution obtained was refluxedfor 4 hours. After cooling to 10° C. there was added dropwise 11.7 ml ofa molar solution of diborane in THF. The whole was stirred at roomtemperature for 16 hours. The reaction mixture was decomposed cautiouslywith 3% HCl; the THF was removed under vacuum at room temperature andthe acid aqueous solution was washed once with ethyl ether, madealkaline with NaHCO₃ and re-extracted with ethyl ether. The organicphase was washed with H₂ O, dried over NaSO₄ and the residue convertedto the hydrochloride which was crystallized from isopropanol and a smallquantity of ethyl ether. There was obtained 2.2 g of2-[α-(2-methoxyphenoxy)-benzyl]-morpholinehydrochloride, melting point140°-170° C. (Yield 84.3%) as a mixture of diastereoisomers in theapproximate ratio of 1:1. The mixture was separated by columnchromatography on silica gel (phase:CHCL₃ /CH₃ OH/HCOOH--160/30/20),thus obtaining two distinct diastereoisomers having melting pointrespectively of 211°-214° C. (diastereoisomer with Rf>) and 175°-178° C.(diastereoisomer with Rf<).

Analogously, all the morpholines unsubstituted in the 4-positionmentioned in Example 20 were prepared.

EXAMPLE 43

2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile in 25ml of anhydrous DMA was stirred with 6.68 g of ethyl bromoacetate in thepresence of 2.76 g of anhydrous potassium carbonate. The mixture washeated at 50° C. for 16 hours, poured into water and extracted withethyl acetate. The organic phase was washed with water, dried over Na₂SO₄ and concentrated to dryness, to obtain 3.55 g of2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)-propionitrile(oil) (Yield 100%), which was used as such for the reaction described inthe previous example.

Analogously, the 2-ethoxycarbonylmethyloxy-propionitriles useful asintermediates to the synthesis of the compounds of Example 42 wereprepared.

EXAMPLE 44

To 3.87 g of2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)-1-nitro-propenein 40 ml of anhydrous THF, at approximately 30° C., there was veryslowly added a solution of 1.7 g of LiAlH₄ in 35 ml of anhydrous THF,under stirring, over approximately 2 hours. After the addition, themixture was refluxed for 2 hours, cooled and treated with water, thenwith 15% soda and then again with water. After filtration, the solid waswashed with THF and the organic solvent was evaporated to dryness. Apurification--HCl (3%), NaOH (20%)--was then made, using ethyl ether assolvent. The residual oil of the concentration was converted into thehydrochloride which was crystallized 3 times from isopropanol plus asmall quantity of ethyl ether, to obtain2-[α-(2-methoxyphenoxy)-benzyl]-morpholine-hydrochloride (1.6 g),melting point 140°-170° C. (Yield 47.8%), as a mixture ofdiastereoisomers in the approximate ratio of 1:1. By means ofchromatography, proceeding as described in Example 42, there wereobtained two distinct diastereoisomers with melting point ofrespectively 211°-214° C. and 175°-178° C.

Analogously, all the morpholines unsubstituted in the 4-positionmentioned in Example 20, except the compounds containing chloro, wereprepared.

EXAMPLE 45

To 3.23 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropenesodium salt dissolved in 50 ml of anhydrous THF there was added at 0° C.16.7 g of ethyl bromoacetate. After 2 hours at 0° C. the mixture wasstirred at room temperature for 48 hours. The mixture was poured intowater and extracted with ethyl acetate. The organic extracts were washedwith water, dried over Na₂ SO₄ and concentrated to dryness. The residuewas separated by column chromatography on silica gel (mobile phase:ethylacetate/cyclohexane 1/1), to obtain 2.70 g of2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene(oil). Yield 70%.

Analogously, all the nitro-propene derivatives useful as intermediatesfor the preparation of the compounds of Example 44 were prepared.

EXAMPLE 46

3.35 g ofN-(2-chloro-ethyl)-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propylaminewas dissolved in 40 ml of anhydrous THF at -10° C. At this temperature,slow dropwise addition was made to the mixture of 6.07 ml of 15% butyllithium in hexane. After approximately 2 hours at -10° C. thetemperature was slowly allowed to return to room temperature and thewhole was stirred for another 20 hours in these conditions, and thenconcentrated to dryness. The residue was dissolved in ethyl ether,filtered and the filtrate again concentrated to dryness. The residue wasconverted to the hydrochloride by treatment with gaseous HCl in ethylether. After three crystallizations from a mixture of isopropanol and avery small quantity of ethyl ether, there was obtained 1.2 g of2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine hydrochloride, melting point112°-170° C. (Yield 35.7%) as a mixture of diastereoisomers. By means ofchromatographic separation, as described in Examples 42 and 44, therewere obtained two distinct diastereoisomers having melting point of211°-214° C. and 175°-178° C. respectively.

Analogously, all the compounds mentioned in the Examples 17, 19 and 20were prepared.

EXAMPLE 47

To a solution ofN-chloro-acetyl-3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine(3.49 g) in anhydrous THF (35 ml), a molar solution of diborane intetrahydrofurane (15 ml) is slowly added dropwise at -5° C. understirring. The mixture was again stirred in cold conditions for 2 hoursand then for 16 hours at room temperature. The mixture was cautiouslydecomposed with a small quantity of 99° ethanol, concentrated to drynessat a temperature below 20° C., to obtainN-(2-chloroethyl)-3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine(3.35 g; 100%) (oil).

This was used immediately as such for the conversion described in theprevious example.

Analogously, all the N-(2-chloroethyl)-propylamines useful asintermediates for the preparation of the compounds of Example 46 wereprepared.

EXAMPLE 48

A mixture of 2.73 g of3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine in 50 ml ofmethylene chloride and 0.56 g of NaOH in 15 ml of water was stirred at0° C. Under vigorous stirring dropwise addition was made to the mixtureover 30 minutes, again at 0° C., of 1.58 g of chloroacetyl chloride in 2ml of methylene chloride. After the addition, the stirring was continuedat 0° C. for 30 minutes. The layers were separated and the aqueous phaseextracted with CH₂ Cl₂. The organic extracts were combined and washedwith water, dried over Na₂ SO₄ and evaporated to dryness. There wasobtained 3.49 g ofN-chloroacetyl-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)propylamine(oil). Yield 100%.

Analogously, all the intermediates useful as starting materials for thepreparation of the compounds of Example 47 were prepared.

EXAMPLE 49

0.82 g of 2-hydroxy-3-phenyl-3-phenoxy-propylamine was stirred at 0° C.with 0.654 g of ethylene glycol dimethanesulphonate in 20 ml ofanhydrous benzene. These conditions were kept for 20 hours. Again at 0°C., under cooling and vigorous stirring, dropwise addition was then madeto the suspension of 3.65 ml of 15% butyl lithium in hexane. The mixturewas kept at 0° C. for 2 hours and then at room temperature for 20 hours.A few drops of water were cautiously added to the mixture, which wasthen evaporated to dryness. A small quantity of water was added to theresidue and the whole was then extracted with ethyl acetate. The organicphase was washed with water, dried over Na₂ SO₄ and evaporated todryness. The residue dissolved in ethyl ether was changed into thehydrochloride by treatment with alcoholic HCl and, after twocrystallizations from a mixture of isopropanol and a small quantity ofethyl ether, there was obtained 0.50 g of 2-(α-phenoxy-benzyl)morpholinehydrochloride, melting point 140°-170° C. Yield 49.4%. Analogously, allthe compounds mentioned in Examples 17, 19 and 20 were prepared.

EXAMPLE 50

To a solution of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine(10 g) in anhydrous dimethylformamide (150 ml), 55% NaH (1.75 g) wasadded at room temperature. After stirring for 1 hour, a solution of2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added allat one time. The temperature was maintained at 50° C. for 1 hour thenNa₂ CO₃ (5.82 g) was added and the whole was maintained at 50° C. for afurther 3 hours. The whole was poured into water and extraction madewith ethyl acetate. After a standard working up, procedure,2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (6.24 g; 57%) was obtainedas a transparent oil. HCl m.p. 140°-170° C. All the compounds mentionedin the Examples 17, 19 and 20 were similarly prepared.

EXAMPLE 51

To 3 g of 2-[α-(2-aminophenoxy)-benzyl]-4-methyl morpholine dissolved in30 ml of acetonitrile there was added 4 ml of 37% aqueous formaldehydeand then 1 g of NaBH₃ CN. Stirring was carried out for 30 minutes atroom temperature and addition was then made of glacial acetic acid toneutrality. The mixture was stirred for 3 hours at room temperature. Thesolvent was removed under vacuum, the residue made alkaline andextracted with chloroform. The chloroform was washed with water toneutrality, the whole was dried and evaporated under reduced pressure.The remained oil was taken up with ethanol to which was added 2 ml of18% alcoholic HCl. Dilution with ethyl ether caused precipitation of2.67 g of 2-[α-(2-N,N-dimethylamino-phenoxy)-benzyl]-4-methyl-morpholinemonohydrochloride (yield 74%).

I.R. νmax (CHCl₃) 2700 cm⁻¹ (NH⁺).

EXAMPLE 52

To a solution of 6.5 g of2-[α-(2-nitro-phenoxy)-benzyl]-4-methylmorpholine in 200 ml of absoluteEtOH there was added 0.7 g of Palladium-charcoal (5%) and the mixturewas hydrogenated at 2.5 atm. for 0.5 hours. The catalyst was filteredout, the solution evaporated to dryness and the residual oil wasconverted to hydrochloride with alcoholic HCl. Crystallization fromEtOAc/EtOH, gave 5.1 g of2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholine mono hydrochloride.Yield 76%.

I.R. νmax (KBr) 3400 cm⁻¹ (NH₂); 2700 cm⁻¹ (NH⁺).

EXAMPLE 53

To a solution of 4.5 g of2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methylmorpholine in 70 ml ofanhydrous DMF there was added 2.2 g of K₂ CO₂ and, at room temperature,slow dropwise addition was made of 1 ml of CH₃ I. After the addition,stirring was carried out for 5 hours at 55° C. The mixture was pouredinto 700 ml of cold water and extracted with ethyl ether. After washingwith NaCl-saturated H₂ O and dehydration with sodium sulphate, the etherextracts were concentrated to a small volume. To the residue there wasadded 18% alcoholic HCl to obtain 4 g of2-[α-(2-methoxy-phenoxy)-benzyl]-4-methyl-morpholine hydrochloride, m.p.67°-90° C. (dec.) (yield 76%).

I.R. ν max (KBr) 2820 cm⁻¹ (OCH₃); 2700 cm⁻¹ (NH⁺).

EXAMPLE 54

To a solution of 15 g of2-[α-(2-amino-phenoxy)-benzyl]-4-methylmorpholine hydrochloride in 50 mlof water there was added 18.5 ml of 23% HCl. The mixture was cooled to0° C. and to it there was then slowly added, under stirring, a solutionof 3.45 g of sodium nitrite in 20 ml of water. After 20 minutes, thetemperature was allowed to rise to room temperature. The whole washeated in a water bath at 40° C. until nitrogen no longer evolved.Extraction was performed with chloroform after adjusting the pH to 9.The organic extracts were dried, and evaporated to dryness and theresidue was dissolved in 5 ml of absolute ethanol. There was added 9 mlof 20% ethanolic HCl. On dilution with a small quantity of ethyl etherthere precipitated 2-[α-(2-hydroxyphenoxy)-benzyl]-4-methyl-morpholinehydrochloride (4.65 g). Yield 31%.

I.R. ν max (KBr) 3500 cm⁻¹ (OH); 2700 cm⁻¹ (NH⁺).

EXAMPLE 55

To 5.1 g of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholine dissolvedin 70 ml of anhydrous toluene there was added 3 ml of ethylchlorocarbonate and the mixture was refluxed for 24 hours. Then it wasevaporated to dryness and there was obtained 5.9 g of oil which wastaken up with 15 ml of 8% alcoholic aqueous HCl and refluxed for 4hours. After evaporation to dryness, the residue was taken up with 50 mlof H₂ O and extraction performed with ethyl ether. After washing with asaturated solution of NaCl and dehydration with sodium sulphate, theether extracts were concentrated to a small volume. By adding alcoholicHCl (18% in absolute EtOH) there was caused to precipitate 3.5 g of2-[α-(2-nitro-phenoxy)-benzyl]-morpholine hydrochloride. Yield 68%.

I.R. ν max 2800 cm⁻¹ (NH); 1525 cm⁻¹ (NO₂).

The compounds of Example 20 were similarly prepared.

EXAMPLE 56

A solution of 4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (5 g)in 99% EtOH (150 ml) and HCl (6 ml) was reduced (palladium-charcoalcatalyst) for 4 hours at room temperature. The mixture was thenfiltered, dried under vacuum and separated on a silica gel column(mobile phase: CHCl₃ :MeOH:NH₄ OH=170:30:2) to obtain2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (2.1 g; yield 54.7%) as atransparent oil. HCl m.p. 140°-170° C.

The morpholine derivatives mentioned in the Example 20 except thosecontaining nitro or chloro were analogously prepared.

EXAMPLE 57

A solution of 4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]morpholine (5 g)in benzene (70 ml) with ethyl chloroformate (1.23 ml) was refluxed for 5hours. The solvent was evaporated and the residue was heated at refluxfor 2 days with 10% KOH (70 ml) in MeOH solution. The whole wasevaporated to dryness and the residue was partitioned between ethylether and water.

The water was extracted with fresh ether. An acid-base purification wasperformed using ether as extraction solvent. Dry over Na₂ SO₄,filtration and evaporation under vacuum gave2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (2.4 g: yield 60%)-as amixture of the diastereoisomers .HCl m.p. 140°-170° C. All the compoundslisted in Example 20 were similarly prepared.

EXAMPLE 58

To a solution of 1.23 g of LiAlH₄ in 50 ml of Et₂ O dropwise additionwas made of 6.8 g of4-benzyl-[α-(2-methoxy-phenoxy)-benzyl]-morpholin-5-one dissolved in 100ml of anhydrous Et₂ O and 30 ml of anhydrous tetrahydrofuran. Thereaction mixture was stirred for two days at room temperature and thenquenched with H₂ O/NaOH/H₂ O and filtered; the solid was washed with hottetrahydrofuran and the filtrate dried over Na₂ SO₄ and then brought tocomplete dryness under vacuum, in this way obtaining4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (4.9 g; yield 78%)as a transparent oil.

Analogously, the 4-benzyl-2-[α-(2-ethoxy-phenoxy)-benzyl]morpholine aswell as the compounds of the Examples 17, 19 and 20, except thosecontaining chloro, were prepared.

EXAMPLE 59

To a solution ofN-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (3.5g) in CH₂ Cl₂ (60 ml), NaOH (0.6 g) and water (16 ml) were added at 0°C. The whole was cooled to -50° C. and chloroacetyl chloride (1.1 ml)diluted in CH₂ Cl₂ (10 ml) was added dropwise. The organic extracts werecombined and washed with a saturated solution of NaCl, drying wascarried out over Na₂ SO₄ and the solution was then evaporated todryness, so obtainingN-benzyl-N-chloroacetyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenylpropylamine(4.0 g; yield 93%) as an oil, chromatographically pure, which is used assuch.

2.5 g of this product was dissolved in dimethyl sulphoxide (10 ml) then55% NaH (0.275 g) was added; after 1.5 hours at room temperature thewhole was poured into water and extracted with EtOAc.

The organic extract was washed several times with water, dried over Na₂SO₄ and evaporated to dryness, so obtaining4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholin-5-one (2.2 g; yield94%).

The 4-benzyl-2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholin-5-one as well asthe 4-benzyl-derivatives useful for the preparation of the compounds ofExample 20, according to the procedure of Examples 56 and 57, weresimilarly prepared.

EXAMPLE 60

(a) To a solution of2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (6 g) in CH₂ Cl₂(70 ml), a solution of NaOH (1.3 g) and water (40 ml) was addeddropwise. Dropwise addition was then made of benzoyl chloride (3.6 ml)dissolved in CH₂ Cl₂ (20 ml) at 0° C. The whole was stirred for 30minutes, the organic layer was separated and the aqueous phase wasextracted with CH₂ Cl₂ ; the combined organic extracts were washed witha saturated aqueous solution of NaCl, dried over Na₂ SO₄ and then thesolution was evaporated to complete dryness, so obtainingN-benzoylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (8.1g; yield 98%) as an oil.

(b) to a solution of LiAlH₄ (16.3 g) in anhydrous Et₂ O (1000 ml) asolution of the oil obtained according to the process under (a) of thepresent example (8.1 g) in anhydrous Et₂ O (1500 ml) was added and thewhole was kept at reflux for 12 hours. After a normal processing and anacid-base purification with Et₂ O as solvent and after evaporation todryness,N-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (35g; yield 45%) was obtained as mixture of diasteroisomers (colourlessoil).

Analogously, theN-benzylamino-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine, aswell as the N-benzylamino-derivatives useful for the preparation of thecompounds of Example 59, were prepared.

EXAMPLE 61

Tablets were prepared, each weighing 200 mg and each containing 25 mg ofactive ingredient, in the manner described below:

Composition (for 10,000 tablets)

2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine: 250 g

Lactose: 1.230 g

Corn starch: 450 g

Talc (powdered): 50 g

Magnesium stearate: 20 g

The 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine, the lactose and half ofthe corn starch were mixed, sieved through a 0.55 mm mesh screen. 30 gof corn starch was dispersed in 300 ml of hot water. The mixture of thepowders was granulated with the starch mucilage obtained. The granulatewas dried and passed through a 1.4 mm mesh screen. The rest of thestarch was added, as also the talc and the magnesium stearate. A carefulblending was performed and the mass was compressed into tablets with 8mm diameter punches.

EXAMPLE 62

Tablets were prepared, each weighing 200 mg and each containing 25 mg ofactive ingredient:

Composition (for 10,000 tablets)

N-methyl-2-methoxy-3-(2-ethoxy-phenoxy)-3-phenyl-propylamine: 250 g

Lactose: 1.230 g

Corn starch: 450 g

Talc (powdered): 50 g

Magnesium stearate: 20 g

The tablets were prepared as described in Example 61.

We claim:
 1. A compound having the following formula (I) ##STR34##wherein n and n₁ are, independently, 1, 2 or 3;one or more of the groupsR and R₁, which may be the same or different, is --NO₂ or ##STR35##wherein R₅ and R₆ are, independently, hydrogen or C₁ -C₆ alkyl, or twoadjacent R groups or two adjacent R₁ groups, taken together, form the--O--CH₂ --O-- radical; and the remainder of the groups R and R₁ arehydrogen; R₃ is (a') hydrogen; (b') C₁ -C₆ alkyl unsubstituted orsubstituted by one or more substituents chosen from the group consistingof halogen, hydroxy, C₁ -C₆ alkoxy, ##STR36## where R₅ and R₆ are asdefined above; (c') C₂ -C₄ alkenyl; C₂ -C₄ alkynyl; (d') phenyl-C₁ -C₄alkyl, in which the phenyl group may be unsubstituted or substituted byone or more substituents chosen from the group consisting of C₁ -C₆alkyl, halogen, halo-C₁ -C₆ alkyl, hydroxy, C₁ -C₆ alkoxy, and ##STR37##wherein R₅ and R₆ are as defined above; (e') C₃ -C₇ cycloalkylunsubstituted or substituted by one or more C₁ -C₆ alkyl, halogen,halo-C₁ -C₆ alkyl, hydroxy, C₁ -Chd 6 alkoxy and ##STR38## where R₅ andR₆ are as defined above; and the pharmaceutically acceptable saltsthereof.
 2. A compound having the following formula (I) ##STR39##wherein n and n₁ are, indpendently, 1, 2 or 3;two adjacent R groups ortwo adjacent R₁ groups, taken together, form the --O--CH₂ --O-- radical,and the other groups R and R₁ are hydrogen; R₃ is (a') hydrogen; (b') C₁-C₆ alkyl unsubstituted or substituted by one or more substituentschosen from the group consisting of halogen, hydroxy, C₁ -C₆ alkoxy,##STR40## where R₅ and R₆ are as defined above; (c') C₂ -C₄ alkenyl; C₂-C₄ alkynyl; (d') phenyl-C₁ -C₄ alkyl, in which the phenyl group may beunsubstituted or substituted by one or more substituents chosen from thegroup consisting of C₁ -C₆ alkyl, halogen, halo-C₁ -C₆ alkyl, hydroxy,C₁ -C₆ alkoxy, and ##STR41## where R₅ and R₆ are as defined above; (e')C₃ -C₇ cycloalkyl unsubstituted or substituted by one or more C₁ -C₆alkyl, halogen, halo-C₁ -C₆ alkyl, hydroxy, C₁ -C₆ alkoxy and ##STR42##where R₅ and R₆ are as defined above; and the pharmaceuticallyacceptable salts thereof.
 3. A compound having the following formula (I)##STR43## wherein n and n₁ are, independently, 1, 2 or 3;two adjacent Rgroups or two adjacent R₁ groups, taken together, form the --O--CH₂--O-- radical, and the other groups R and R₁ are hydrogen; R₃ ishydrogen, methyl or isopropyl;and the pharmaceutically acceptable saltsthereof.
 4. 2-[α-(3,4-methylendioxy-phenoxy)-benzyl]-morpholine and thepharmaceutically acceptable salts thereof.
 5. A salt of the compound ofclaim 3 wherein the salt is the hydrochloride.
 6. A compound having thefollowing formula (I) ##STR44## wherein n and n₁ are, independently, 1,2 or 3;one or more of the groups R and R₁, which may be the same ordifferent, is --NO₂ or ##STR45## wherein R₅ and R₆ are, independently,hydrogen or C₁ -C₆ alkyl, and the remainder of the groups R and R₁ arehydrogen; R₃ is (a') hydrogen; (b') C₁ -C₆ alkyl unsubstituted orsubstituted by one or more substituents chosen from the group consistingof halogen, hydroxy, C₁ -C₆ alkoxy, ##STR46## where R₅ and R₆ are asdefined above; (c') C₂ -C₄ alkenyl; C₂ -C₄ alkynyl; (d') phenyl-C₁ -C₄alkyl, in which the phenyl group may be unsubstituted or substituted byone or more substituents chosen from the group consisting of C₁ -C₆alkyl, halogen, halo-C₁ -C₆ alkyl, hydroxy, C₁ -C₆ alkoxy, and ##STR47##where R₅ and R₆ are as defined above; (e') C₃ -C₇ cycloalkylunsubstituted or substituted by one or more C₁ -C₆ alkyl, halogen,halo-C₁ -C₆ alkyl, hydroxy, C₁ -C₆ alkoxy and ##STR48## where R₅ and R₆are as defined above; and the pharmaceutically acceptable salts thereof.7. A compound selected from the group consistingof:2-[α-(2-N,N-dimethylamino-phenoxy)-benzyl]-4-methyl-morpholine;2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholine;2-[α-(2-nitro-phenoxy)-benzyl]-morpholine,and the pharmaceuticallyacceptable salts thereof.
 8. An antidepressant composition comprising anantidepressant effective amount of a compound according to any one ofclaims 1-7 and a pharmaceutically acceptable carrier and/or diluent.